Heterocyclic compounds and methods of use thereof

ABSTRACT

Provided herein are heterocyclic compounds for treatment of CSF1R, FLT3, KIT, and/or PDGFRβ kinase mediated diseases. Also provided are pharmaceutical compositions comprising the compounds and methods of using the compounds and compositions.

RELATED APPLICATIONS

This application claims priority to U.S. provisional application No.61/547,637, filed in Oct. 14, 2011 and U.S. provisional application No.61/638,990, filed in Apr. 26, 2012. The disclosures of each the abovereferenced applications are incorporated by reference herein in theirentireties.

FIELD

Provided herein are heterocyclic compounds, including benzothiazolyl,benzoxazolyl, and quinazolyl compounds. In certain embodiments, thecompounds are modulators of type III receptor tyrosine kinase family. Inother embodiments, the compounds are modulators of CSF1R, FLT3, KIT,and/or PDGFRβ kinases. Also provided are compositions comprising thecompounds and methods of use thereof. The compounds provided are usefulin the treatment, prevention, or amelioration of a disease or disorderrelated to CSF1R, FLT3, KIT, and/or PDGFRβ kinase activity or one ormore symptoms associated with such diseases or disorders.

BACKGROUND

Protein kinases (PKs) are enzymes that catalyze the phosphorylation ofhydroxy groups on tyrosine, serine and threonine residues of proteins.Receptor tyrosine kinases (RTKs) are a sub-family of protein kinasesthat play a critical role in cell signaling and are involved in theprocess of tumorigenesis including cell proliferation, survival,angiogenesis, invasion and metastasis. A class of RTK known as the typeIII receptor tyrosine kinase family, which includes the receptors PDGFRα, PDGFR β, FLT3, KIT, VEGFR and CSF1R, has been implicated in variousproliferative and inflammatory diseases.

CSF1R (also known as macrophage colony stimulating factor receptor(M-CSFR) or fms) is a receptor for the macrophage colony stimulatingfactor (M-CSF or CSF-1). Binding of the CSF-1 ligand to its receptorresults in dimerization and auto-phosphorylation of the receptor andleads to activation of downstream signal transduction pathways includingthe PI3K/Akt and the mitogen activating protein kinase MAPK pathways.Activation of CSF1R leads to the proliferation, survival, motility anddifferentiation of cells of the monocyte/macrophage lineage and henceplays a role in normal tissue development and immune defense. Activationof CSF1R also leads to the proliferation and differentiation ofosteoclast precursors and therefore mediates the process of boneresorption.

Because of its role in osteoclast biology, CSF1R is believed to be animportant therapeutic target for osteoporosis and inflammatoryarthritis. For example, elevated M-CFS signaling leads to elevatedosteoclast activity, which leads to bone loss attending arthritis andother inflammatory bone erosion. (See Scott et al. Rheumatology 2000,39: 122-132, Ritchlin et al. J. Clin. Invest. 2003, 111:821-831).Inhibition of CSF1R therefore represents a promising therapeuticapproach for arthritis and other inflammatory bone erosion which isfurther supported by the efficacy data of known CSF1R inhibitors such asKi-20227 and GW2580 in arthritic animal models (See Conwat et al. JPET2008, 326:41-50 and Ohno et al. Eur. J. Immunol. 2008, 38:283-291).Dysregulation of osteoclast development and disruption in the balance ofbone resorption and bone formation that underlie osteoporosis might alsobe treated with a modulator of CSF1R.

Elevated expression or activation of CSF1R and/or its ligand have beenfound in patients with acute myeloid leukemia, prostate, breast,ovarian, endometrial, colorectal, pancreatic and a variety of othercancers, and elevated levels of M-CSF is associated with poor prognosisin certain cancers (See, Muller-Tidow et al. Clin Cancer Res, 2004,10:1241-1249, Bauknecht et al. Cancer Detect. Prev., 1994, 18: 231-239;Baiocchi G et al. Cancer 1991, 67:990-996; Kirma et al Cancer Res. 2007;Sapi et al. Exp. Biol. Med., 2004, 229:1-11; Kluger et al. Clin. Canc.Res. 2004 10:173-177; Mroczko et al., Clin. Chem. Lab. Med. 200543:146-50 and Mroczko et al., Clin. Chim. Acta 2007, 380:208-212). Thedata suggests that CSF1R may be a valuable therapeutic target for thesesolid tumors.

Early studies have associated elevated expression of M-CSF withincreased leukocyte infiltration of solid tumors in human breast andovarian cancers (Scholl et al. J. Natl. Cancer Inst. 1994, 86:120-126,Tang et al. J. Cell. Biochem. 1990, 44:189-198). Further studies haveshown that M-CSF is one of several cytokines implicated in therecruitment of tumor-associated macrophages (TAMs) that contribute totumor angiogenesis and tumor progression to metastasis, and morerecently, that the preclinical inhibitor GW2580 inhibits tumormetastasis and angiogenesis in mice tumor xenograft experiments(Priceman et al. Blood 2010 115(7):1461-1471). Stimulated osteoclastactivity is also believed to underlie the pathophysiology of bonemetastases. (Lipton, J. Support. Oncol. 2004 2:205-220). Metastatic bonelesions results in significant localized bone loss and lead to skeletalmorbidity, symptoms which include bone pain, bone fractures andhypercalcemia. Inhibition of CSF1R therefore may therefore providetherapy for solid tumors and metastatic cancer including metastases tothe bone.

Another member of the PDGFR family, FLT3 (also called Flk2), plays animportant role in the proliferation and differentiation of hematopoieticstem cells and activating mutation or overexpression of this receptor isfound in AML (See, Heinrich Mini-Reviews in Medicinal Chemistry 2004,4(3):255-271, Kiyoi et al. Int J Hematol, 2005 82:85-92). More than adozen known FLT3 inhibitors are being developed and some have shownpromising clinical effects against AML (See Levis et al. Int J Hematol.2005 82:100-107). The FLT3 receptor is also expressed in a large portionof dendritic cell progenitors and stimulation of the receptor causes theproliferation and differentiation of these progenitors into dendriticcells (DC). Since dendritic cells are the main initiators of the T-cellmediated immune response, including the autoreactive immune response,FLT3 inhibition is a mechanism for downregulating DC-mediatedinflammatory and autoimmune responses. One study shows the FLT3inhibitor CEP-701 to be effective in reducing myelin loss inexperimental autoimmune encephalomyelitis (EAE), a mouse model formultiple sclerosis (See Whartenby et al. PNAS 2005 102: 16741-16746). Ahigh level of the FLT3 ligand is found in the serum of patients withLangerhans cell histiocytosis and systemic lupus erythematosus, whichfurther implicates FLT3 signaling in the dysregulation of dendritic cellprogenitors in those autoimmune diseases (See Rolland et al. J. Immunol.2005 174:3067-3071).

KIT (or stem cell factor receptor, or SCFR) is another member of the RTKfamily, and the presence of kit mutations is a key diagnostic marker forgastrointestinal stromal tumors (GIST) (Duensing et al. CancerInvestigation 2004, 22(1): 106-116). Gleevec® (imatinib mesylate orSTI571), the first FDA-approved RTK inhibitor originally approved forc-Abl-mediated chronic myeloid leukemia, gained FDA-approval forKIT-mediated GIST in 2002 and has validated the molecular-based approachof Kit inhibition for the treatment of GIST. (Giorgi and Verweij, Mol.Cancer Ther. 2005 4(3):495-501). Gain of function mutations of the Kitreceptor are also associated with mast cell/myeloid leukemia andseminomas/dysgerminomas (Blume-Jensen Nature 2001 411(17): 355-365. KITmutations have been also identified in certain melanomas and isrecognized as a potential therapeutic target for melanoma (Curtain etal. J Clin. Oncol. 2006 24(26):4340-4346).

There continues to be a need for the identification of small moleculesthat inhibit RTKs, particularly compounds useful for the treatment ofCSF1R-, FLT3, PDGFRβ- and/or KIT-mediated diseases.

SUMMARY

Provided herein are compounds of formula (I) or pharmaceuticallyacceptable salts, solvates, hydrates, clathrates, single stereoisomers,mixture of stereoisomers or racemic mixture of stereoisomers thereof. Incertain embodiment, the compounds have activity as CSF1R, FLT3, KIT,and/or PDGFRβ kinase modulators. The compounds are useful in medicaltreatments, pharmaceutical compositions and methods for modulating theactivity of CSF1R, FLT3, KIT, and/or PDGFRβ kinases, including wildtypeand/or mutated forms of CSF1R, FLT3, KIT, and/or PDGFRβ kinases. Incertain embodiments, the compounds provided herein have activity asCSF1R, FLT3, KIT, and/or PDGFRβ kinase modulators. In one embodiment,the compounds for use in the compositions and methods provided hereinhave formula (I).

In certain embodiments, provided herein are compounds of Formula I:

or pharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof, wherein:

R¹ and R² are each independently selected from hydrogen, deuterium,halogen, hydroxyl and alkoxy, or R¹ and R² together form ═O;

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl, whereR⁴ is optionally substituted with one or more, in one embodiment, one tothree, in another embodiment, one, two or three groups selected from Q¹;

each Q¹ is independently deuterium, halo, cyano, oxo, thioxo, alkyl,haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w), ═NOR^(d), or —C(═NR^(y))N(R^(y))OR^(x),where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q³ groups, in one embodiment, one to threeQ³ groups; each Q³ is independently selected from deuterium, halo,hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, deuterium, halo, alkyl,haloalkyl or hydroxyalkyl;

Z is O, S or NR⁷;

R⁷ is hydrogen, deuterium or alkyl;

each W is independently CR⁸ or N;

R⁸ is hydrogen, deuterium, halo, haloalkyl or alkyl;

ring A is a bicyclic or tricyclic aryl, heteroaryl or heterocyclyloptionally substituted with one to four substituents selected from Q²;

W¹ is N or C;

W² is N, NR^(9a) or CR^(9b);

W³ is N, NR^(10a) or CR^(10b);

W⁴ is N, NR^(11a) or CR^(11b);

R^(9a), R^(9b), R^(10a), R^(10b), R^(11a) and R^(11b) are selected asfollows:

-   -   i) R^(9a), R^(10a) and R^(11a) are each independently hydrogen,        deuterium or alkyl and R^(9b), R^(10b) and R^(11b) are each        independently hydrogen or Q²; or    -   ii) R^(9a) and R^(10b), R^(9a) and R^(10a), R^(9b) and R^(10b),        R^(9b) and R^(10a), R^(10b) and R^(11a), R^(10a) and R^(11b),        R^(10a) and R^(11b) or R^(10b) and R^(11b) together with the        atoms to which they are attached form an aryl, heteroaryl or        heterocyclyl ring, optionally substituted with one or more, in        one embodiment, one to three, in another embodiment, one, two or        three groups selected from Q²; and the remainder of R^(9a) or        R^(11a) is hydrogen, deuterium or alkyl; and the remainder of        R^(9b) or R^(11b) is hydrogen or Q²; or    -   iii) R^(9a) and R^(10b), R^(9a) and R^(10a), R^(9b) and R^(10b),        R^(9b) and R^(10a), R^(10b) and R^(11a), R^(10a) and R^(11b),        R^(10a) and R^(11b) or R^(10b) and R^(11b) together with the        atoms to which they are attached form an aryl, heteroaryl or        heterocyclyl ring optionally fused to a phenyl ring optionally        substituted with one or more, in one embodiment, one to three,        in another embodiment, one, two or three groups selected from        Q²; and the remainder of R^(9a) or R^(11a) is hydrogen,        deuterium or alkyl and the remainder of R^(9b) or R^(11b) is        hydrogen or Q²;

each Q² is independently halo, deuterium, cyano, oxo, thioxo, alkyl,haloalkyl, haloalkenyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl,—R^(u)OR^(x), —R^(u)OR^(u)OR^(x), —R^(u)OR^(u)N(R^(y))(R^(z)),R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x), —R^(u)C(J)R^(x), —R^(u)C(J)OR^(x),—R^(u)C(J)N(R^(y))(R^(z)), —R^(u)C(J)R^(u)N(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —C(═NOR^(x))R^(x), —R^(u)S(O)_(t)R^(w),—R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w) or —C(═NR^(y))N(R^(y))OR^(x), where thealkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more groups Q⁴; in one embodiment, one to threeQ⁴ groups, each Q⁴ is independently selected from halo, deuterium,hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

each R^(d) is independently hydrogen or alkyl;

each R^(u) is independently alkylene, alkenylene or a direct bond;

R^(w) is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl;

each R^(x) is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl;

R^(y) and R^(z) are each independently selected from (i) or (ii) below:

-   -   (i) R^(y) and R^(z) are each independently hydrogen, alkyl,        haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl,        cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl,        heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or        heteroaralkyl; or    -   (ii) R^(y) and R^(z), together with the nitrogen atom to which        they are attached, form a heterocyclyl or heteroaryl, optionally        substituted with one or more, in one embodiment, one, two or        three Q⁷ groups; each Q⁷ is independently selected from halo,        deuterium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl,        hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,        cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl,        heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2;

n is 1 or 2; and

q is an integer from 0-4,

wherein the compounds are selected such that: i) when W is CH; W¹ is C;Z is S; R¹ is hydrogen, or hydroxyl and R² is hydrogen, or R¹ and R²together form ═O; then ring A is not pyridine; ii) when W is CH; W¹ isN; Z is S; R¹ and R² are hydrogen, then ring A is not pyrrolidine; iii)when W is CH, Z is NH, R¹ and R² together form ═O, q is 0, and R⁴ ispyridinyl, then ring A is not phenyl, iv) when W is CH, Z is NH, R¹ andR² together form ═O, q is 0, and R⁴ is phenyl, then ring A is notpyrrolidine, and v) when Z is N, one of R¹ and R² is methyl and theother of R¹ and R² is H, q is 0, and R³ is pyridine, and W¹ is N, ring Acannot be piperidine, 1,2,3,4-tetrahydroisoquinoline, or isoindoline.

In one embodiment, the compound provided herein is a compound of formula(I). In one embodiment, the compound provided herein is apharmaceutically acceptable salt of the compound of formula (I). In oneembodiment, the compound provided herein is a solvate of the compound offormula (I). In one embodiment, the compound provided herein is ahydrate of compound of formula (I). In one embodiment, the compoundprovided herein is a prodrug of the compound of formula (I). In oneembodiment, the compound provided herein is a clathrate of the compoundof formula (I).

Also provided are pharmaceutical compositions formulated foradministration by an appropriate route and means containing effectiveconcentrations of one or more of the compounds provided herein, orpharmaceutically acceptable salts, solvates, hydrates and prodrugsthereof, and optionally comprising at least one pharmaceutical carrier.

In one embodiment, the pharmaceutical compositions deliver amountseffective for the treatment, prevention, or amelioration of diseases ordisorders that are modulated or otherwise affected by CSF1R, FLT3, KIT,and/or PDGFRβ kinases, or one or more symptoms or causes thereof. Suchdiseases or disorders include without limitation, cancers, nonmalignantproliferation diseases, atherosclerosis, restenosis following vascularangioplasty, fibroproliferative disorders, inflammatory diseases ordisorders related to immune dysfunction, infectious diseases, and/ordiseases or disorders that can be treated, prevented or managed bymodulating the activity, binding or sub-cellular distribution ofkinases, wherein such methods comprise administering to a subject, e.g.,a human, in need of such treatment, prevention or management atherapeutically and prophylactically effective amount of a compoundprovided herein. Such diseases or disorders are further describedherein.

Also provided herein are combination therapies using one or morecompounds or compositions provided herein, or pharmaceuticallyacceptable derivatives thereof, in combination with otherpharmaceutically active agents for the treatment of the diseases anddisorders described herein.

In one embodiment, such additional pharmaceutical agents include one ormore chemotherapeutic agents, anti-proliferative agents,anti-inflammatory agents, immunomodulatory agents or immunosuppressiveagents.

The compounds or compositions provided herein, or pharmaceuticallyacceptable derivatives thereof, may be administered simultaneously with,prior to, or after administration of one or more of the above agents.Pharmaceutical compositions containing a compound provided herein andone or more of the above agents are also provided.

In certain embodiments, provided herein are methods of treating,preventing or ameliorating a disease or disorder that is modulated orotherwise affected by CSF1R, FLT3, KIT, and/or PDGFRβ kinases such aswild type and/or mutant CSF1R, FLT3, KIT, and/or PDGFRβ kinases, or oneor more symptoms or causes thereof.

In practicing the methods, effective amounts of the compounds orcompositions containing therapeutically effective concentrations of thecompounds, which are formulated for systemic delivery, includingparenteral, oral, or intravenous delivery, or for local or topicalapplication are administered to an individual exhibiting the symptoms ofthe disease or disorder to be treated. The amounts are effective toameliorate or eliminate one or more symptoms of the disease or disorder.

Further provided is a pharmaceutical pack or kit comprising one or morecontainers filled with one or more of the ingredients of thepharmaceutical compositions. Optionally associated with suchcontainer(s) can be a notice in the form prescribed by a governmentalagency regulating the manufacture, use or sale of pharmaceuticals orbiological products, which notice reflects approval by the agency ofmanufacture, use of sale for human administration. The pack or kit canbe labeled with information regarding mode of administration, sequenceof drug administration (e.g., separately, sequentially or concurrently),or the like.

These and other aspects of the subject matter described herein willbecome evident upon reference to the following detailed description.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 depicts the in vivo inhibition of CSF-1 dependent M-NFS-60 tumorcell proliferation in the peritoneal cavity of athymic nu/nu mice fromthe administration of one of the compounds provided herein having theFormula I (Compound A).

FIG. 2 depicts the in vivo inhibition of CSF-1 dependent M-NFS-60 tumorcell proliferation in the peritoneal cavity of athymic nu/nu mice fromthe administration of one of the compounds provided herein having theFormula I (Compound B).

FIG. 3 depicts the in vivo inhibition of PTHrP-induced hypercalcemiafrom the administration of Compound A having the Formula I, in BDF1 micechallenged twice daily for seven days with 0.5 mg/kg recombinant PTHrP,as measured by serum TRAPC5B levels, a bone resorption marker.

FIG. 4 depicts the in vivo inhibition of PTHrP-induced hypercalcemiafrom the administration of Compound B having the Formula I, in BDF1 micechallenged twice daily for seven days with 0.5 mg/kg recombinant PTHrP,as measured by serum TRAPC5B levels, a bone resorption marker.

FIG. 5 depicts the in vivo inhibition of MCP-1 induction in Balb/c micetreated with Compound A having the Formula I, prior to M-CSFstimulation.

FIG. 6 depicts the in vivo inhibition of MCP-1 induction in Balb/c micetreated with Compound B having the Formula I, prior to M-CSFstimulation.

DETAILED DESCRIPTION

Provided herein are compounds of formula I that have activity as CSF1R,FLT3, KIT, and/or PDGFRβ kinase modulators. Further provided are methodsof treating, preventing or ameliorating diseases that are modulated byCSF1R, FLT3, KIT, and/or PDGFRβ kinases, and pharmaceutical compositionsand dosage forms useful for such methods. The methods and compositionsare described in detail in the sections below.

A. DEFINITIONS

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art. All patents, applications, published applications and otherpublications are incorporated by reference in their entirety. In theevent that there are a plurality of definitions for a term herein, thosein this section prevail unless stated otherwise.

“Alkyl” refers to a straight or branched hydrocarbon chain groupconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to ten, one to eight, one to six or one tofour carbon atoms, and which is attached to the rest of the molecule bya single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl(iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), and thelike.

“Alkenyl” refers to a straight or branched hydrocarbon chain groupconsisting solely of carbon and hydrogen atoms, containing at least onedouble bond, having from two to ten carbon atoms, and which is attachedto the rest of the molecule by a single bond or a double bond, e.g.,ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and thelike.

“Alkynyl” refers to a straight or branched hydrocarbon chain groupconsisting solely of carbon and hydrogen atoms, containing at least onetriple bond, having from two to ten carbon atoms, and which is attachedto the rest of the molecule by a single bond or a triple bond, e.g.,ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-ynyl, pent-3-ynyl and the like.

“Alkylene” and “alkylene chain” refer to a straight or branched divalenthydrocarbon chain consisting solely of carbon and hydrogen, containingno unsaturation and having from one to eight carbon atoms, e.g.,methylene, ethylene, propylene, n-butylene and the like. The alkylenechain may be attached to the rest of the molecule through any twocarbons within the chain.

“Alkenylene” or “alkenylene chain” refers to a straight or branchedchain unsaturated divalent radical consisting solely of carbon andhydrogen atoms, having from two to eight carbon atoms, wherein theunsaturation is present only as double bonds and wherein the double bondcan exist between any two carbon atoms in the chain, e.g., ethenylene,prop-1-enylene, but-2-enylene and the like. The alkenylene chain may beattached to the rest of the molecule through any two carbons within thechain.

“Alkynylene” or “alkynylene chain” refers to a straight or branchedchain unsaturated divalent radical consisting solely of carbon andhydrogen atoms, having from two to eight carbon atoms, wherein theunsaturation is present only as triple bonds and wherein the triple bondcan exist between any two carbon atoms in the chain, e.g., ethynylene,prop-1-ynylene, but-2-ynylene, pent-1-ynylene, pent-3-ynylene and thelike. The alkynylene chain may be attached to the rest of the moleculethrough any two carbons within the chain.

“Alkoxy” refers to the group having the formula —OR wherein R is alkylor haloalkyl. An “optionally substituted alkoxy” refers to the grouphaving the formula —OR wherein R is an optionally substituted alkyl asdefined herein.

“Amino” refers to a radical having the formula —NR′R″ wherein R′ and R″are each independently hydrogen, alkyl or haloalkyl. An “optionallysubstituted amino” refers to a radical having the formula —NR′R″ whereinone or both of R′ and R″ are optionally substituted alkyl as definedherein.

“Aryl” refers to a group of carbocylic ring system, includingmonocyclic, bicyclic, tricyclic, tetracyclic C₆-C₁₈ ring systems,wherein at least one of the rings is aromatic. The aryl may be fullyaromatic, examples of which are phenyl, naphthyl, anthracenyl,acenaphthylenyl, azulenyl, fluorenyl, indenyl and pyrenyl. The aryl mayalso contain an aromatic ring in combination with a non-aromatic ring,examples of which are acenaphene, indene, and fluorene.

“Cycloalkyl” refers to a stable monovalent monocyclic or bicyclichydrocarbon group consisting solely of carbon and hydrogen atoms, havingfrom three to ten carbon atoms which is saturated, e.g., cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, decalinyl, norbornane, norbornene,adamantyl, bicyclo[2.2.2]octane and the like.

“Cycloalkenyl” refers to a stable monovalent monocyclic or bicyclichydrocarbon group consisting solely of carbon and hydrogen atoms, havingfrom three to ten carbon atoms, which is partially unsaturated. Examplesof cycloalkenyl include cyclopropene, cyclobutylene, cyclopentene andcyclohexene.

“Halo, “halogen” or “halide” refers to F, Cl, Br or I.

“Haloalkyl” refers to an alkyl group, in certain embodiments, C₁-6alkylgroup in which one or more of the hydrogen atoms are replaced byhalogen. Such groups include, but are not limited to, chloromethyl,trifluoromethyl 1-chloro-2-fluoroethyl, 2,2-difluoroethyl,2-fluoropropyl, 2-fluoropropan-2-yl, 2,2,2-trifluoroethyl,1,1-difluoroethyl, 1,3-difluoro-2-methylpropyl, 2,2-difluorocyclopropyl,(trifluoromethyl)cyclopropyl, 4,4-difluorocyclohexyl and2,2,2-trifluoro-1,1-dimethyl-ethyl.

“Heterocycle” or “Heterocyclyl” refers to a stable 3- to 15-memberednon-aromatic ring radical which consists of carbon atoms and from one tofive heteroatoms selected from a group consisting of nitrogen, oxygenand sulfur. In one embodiment, the heterocyclic ring system radical maybe a monocyclic, bicyclic or tricyclic ring or tetracyclic ring system,which may include fused or bridged ring systems; and the nitrogen orsulfur atoms in the heterocyclic ring system radical may be optionallyoxidized; the nitrogen atom may be optionally quaternized; and theheterocyclyl radical may be partially or fully saturated. Theheterocyclic ring system may be attached to the main structure at anyheteroatom or carbon atom which results in the creation of a stablecompound. Exemplary heterocylic radicals include, morpholinyl,piperidinyl, piperazinyl, pyranyl, pyrrolidinyl, oxetanyl, azetidinyl,quinuclidinyl, octahydroquinolizinyl, decahydroquinolizinyl,azabicyclo[3.2.1]octanyl, azabicyclo[2.2.2]octanyl, isoindolinyl,indolinyl and others.

“Heteroaryl” refers to a heterocyclyl group as defined above which isaromatic. The heteroaryl groups include, but are not limited tomonocyclyl, bicyclyl and tricyclyl groups, and may be attached to themain structure at any heteroatom or carbon atom which results in thecreation of a stable compound. Examples of such heteroaryl groupsinclude, but are not limited to: furanyl, imidazolyl, oxazolyl,isoxazolyl, pyrimidinyl, pyridinyl, pyridazinyl, thiazolyl, thienyl,benzimidazolyl, imidazo[4,5-b]pyridinyl, imidazo[1,2-a]pyridinyl,imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl and others.

“Heterocyclylalkyl” refers to a group of the formula —R_(a)R_(e) whereinR_(a) is an alkyl group as defined above and R_(e) is a heterocyclylgroup as defined herein, where the alkyl group R_(a) may attach ateither the carbon atom or the heteroatom of the heterocyclyl groupR_(e). The alkyl group and the heterocyclyl group may be optionallysubstituted as defined herein.

“IC₅₀” refers to an amount, concentration or dosage of a particular testcompound that achieves a 50% inhibition of a maximal response, such ascell growth or proliferation measured via any the in vitro or cell basedassay described herein.

“Oxo” refers to the group ═O attached to a carbon atom.

Pharmaceutically acceptable salts include, but are not limited to, aminesalts, such as but not limited to N,N′-dibenzylethylenediamine,chloroprocaine, choline, ammonia, diethanolamine and otherhydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine,N-benzylphenethylamine,1-para-chlorobenzyl-2-pyrrolidin-1′-ylmethyl-benzimidazole, diethylamineand other alkylamines, piperazine and tris(hydroxymethyl)aminomethane;alkali metal salts, such as but not limited to lithium, potassium andsodium; alkali earth metal salts, such as but not limited to barium,calcium and magnesium; transition metal salts, such as but not limitedto zinc; and other metal salts, such as but not limited to sodiumhydrogen phosphate and disodium phosphate; and also including, but notlimited to, salts of mineral acids, such as but not limited tohydrochlorides and sulfates; and salts of organic acids, such as but notlimited to acetates, lactates, malates, tartrates, citrates, ascorbates,succinates, butyrates, valerates, fumarates and organic sulfonates.

As used herein and unless otherwise indicated, the term “hydrate” meansa compound provided herein or a salt thereof, that further includes astoichiometric or non-stoichiometeric amount of water bound bynon-covalent intermolecular forces.

As used herein and unless otherwise indicated, the term “solvate” meansa solvate formed from the association of one or more solvent moleculesto a compound provided herein. The term “solvate” includes hydrates(e.g., mono-hydrate, dihydrate, trihydrate, tetrahydrate and the like).

As used herein, “substantially pure” means sufficiently homogeneous toappear free of readily detectable impurities as determined by standardmethods of analysis, such as thin layer chromatography (TLC), gelelectrophoresis, high performance liquid chromatography (HPLC) and massspectrometry (MS), used by those of skill in the art to assess suchpurity, or sufficiently pure such that further purification would notdetectably alter the physical and chemical properties, such as enzymaticand biological activities, of the substance. Methods for purification ofthe compounds to produce substantially chemically pure compounds areknown to those of skill in the art. A substantially chemically purecompound may, however, be a mixture of stereoisomers. In such instances,further purification might increase the specific activity of thecompound.

Unless stated otherwise specifically described in the specification, itis understood that the substitution can occur on any atom of the alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group.

Unless specifically stated otherwise, where a compound may assumealternative tautomeric, regioisomeric and/or stereoisomeric forms, allalternative isomers are intended to be encompassed within the scope ofthe claimed subject matter. For example, where a compound is describedas having one of two tautomeric forms, it is intended that the bothtautomers be encompassed herein.

Thus, the compounds provided herein may be enantiomerically pure, or bestereoisomeric or diastereomeric mixtures.

It is to be understood that the compounds provided herein may containchiral centers. Such chiral centers may be of either the (R) or (S)configuration, or may be a mixture thereof. It is to be understood thatthe chiral centers of the compounds provided herein may undergoepimerization in vivo. As such, one of skill in the art will recognizethat administration of a compound in its (R) form is equivalent, forcompounds that undergo epimerization in vivo, to administration of thecompound in its (S) form.

Optically active (+) and (−), (R)- and (S)-, or (D)- and (L)-isomers maybe prepared using chiral synthons or chiral reagents, or resolved usingconventional techniques, such as chromatography on a chiral stationaryphase.

As used herein, “isotopic composition” refers to the amount of eachisotope present for a given atom, and “natural isotopic composition”refers to the naturally occurring isotopic composition or abundance fora given atom. Atoms containing their natural isotopic composition mayalso be referred to herein as “non-enriched” atoms. Unless otherwisedesignated, the atoms of the compounds recited herein are meant torepresent any stable isotope of that atom. For example, unless otherwisestated, when a position is designated specifically as “H” or “hydrogen”,the position is understood to have hydrogen at its natural isotopiccomposition.

As used herein, “isotopically enriched” refers to an atom having anisotopic composition other than the natural isotopic composition of thatatom. “Isotopically enriched” may also refer to a compound containing atleast one atom having an isotopic composition other than the naturalisotopic composition of that atom.

As used herein, “isotopic enrichment” refers to the percentage ofincorporation of an amount of a specific isotope at a given atom in amolecule in the place of that atom's natural isotopic abundance. Forexample, deuterium enrichment of 1% at a given position means that 1% ofthe molecules in a given sample contain deuterium at the specifiedposition. Because the naturally occurring distribution of deuterium isabout 0.0156%, deuterium enrichment at any position in a compoundsynthesized using non-enriched starting materials is about 0.0156%. Theisotopic enrichment of the compounds provided herein can be determinedusing conventional analytical methods known to one of ordinary skill inthe art, including mass spectrometry and nuclear magnetic resonancespectroscopy.

Where the number of any given substituent is not specified (e.g.,haloalkyl), there may be one or more substituents present. For example,“haloalkyl” may include one or more of the same or different halogens.

In the description herein, if there is any discrepancy between achemical name and chemical structure, the structure controls.

“Anti-cancer agents” refers to anti-metabolites (e.g., 5-fluoro-uracil,methotrexate, fludarabine), antimicrotubule agents (e.g., vincaalkaloids such as vincristine, vinblastine; taxanes such as paclitaxel,docetaxel), alkylating agents (e.g., cyclophosphamide, melphalan,carmustine, nitrosoureas such as bischloroethylnitrosurea andhydroxyurea), platinum agents (e.g. cisplatin, carboplatin, oxaliplatin,JM-216 or satraplatin, CI-973), anthracyclines (e.g., doxrubicin,daunorubicin), antitumor antibiotics (e.g., mitomycin, idarubicin,adriamycin, daunomycin), topoisomerase inhibitors (e.g., etoposide,camptothecins), anti-angiogenesis agents (e.g. Sutent® and Bevacizumab)or any other cytotoxic agents, (estramustine phosphate, prednimustine),hormones or hormone agonists, antagonists, partial agonists or partialantagonists, kinase inhibitors, and radiation treatment.

“Anti-inflammatory agents” refers to matrix metalloproteinaseinhibitors, inhibitors of pro-inflammatory cytokines (e.g., anti-TNFmolecules, TNF soluble receptors, and IL1) non-steroidalanti-inflammatory drugs (NSAIDs) such as prostaglandin synthaseinhibitors (e.g., choline magnesium salicylate, salicylsalicyclic acid),COX-1 or COX-2 inhibitors), or glucocorticoid receptor agonists such ascorticosteroids, methylprednisone, prednisone, or cortisone.

As used herein, the abbreviations for any protective groups, amino acidsand other compounds, are, unless indicated otherwise, in accord withtheir common usage, recognized abbreviations, or the IUPAC-IUBCommission on Biochemical Nomenclature (see, Biochem. 1972, 11:942-944).

B. COMPOUNDS

In certain embodiments, provided herein are compounds of Formula I:

or pharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof, wherein:

R¹ and R² are each independently selected from hydrogen, deuterium,halogen, hydroxyl and alkoxy, or R¹ and R² together form ═O;

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl, whereR⁴ is optionally substituted with one or more, in one embodiment, one tothree, in another embodiment, one, two or three groups selected from Q¹;

each Q¹ is independently deuterium, halo, cyano, oxo, thioxo, alkyl,haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w), ═NOR^(d), or —C(═NR^(y))N(R^(y))OR^(x),where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q³ groups, in one embodiment, one to threeQ³ groups; each Q³ is independently selected from deuterium, halo,hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, deuterium, halo, alkyl,haloalkyl or hydroxyalkyl;

Z is O, S or NR⁷;

R⁷ is hydrogen, deuterium or alkyl;

each W is independently CR⁸ or N;

R⁸ is hydrogen, deuterium, halo or alkyl;

ring A is a monocyclic, bicyclic or tricyclic aryl, heteroaryl orheterocyclyl optionally substituted with one to four substituentsselected from Q²;

W¹ is N or C;

W² is N, NR^(9a) or CR^(9b);

W³ is N, NR^(10a) or CR^(10b);

W⁴ is N, NR^(11a) or CR^(11b);

R^(9a), R^(9b), R^(10a), R^(10b), R^(11a) and R^(11b) are selected asfollows:

-   -   i) R^(9a), R^(10a) and R^(11a) are each independently hydrogen        or alkyl and R^(9b), R^(10b) and R^(11b) are each independently        hydrogen, deuterium, oxo, hydroxyl, halo or alkyl; or    -   ii) R^(9a) and R^(10b), R^(9b) and R^(10b), R^(9b) and R^(10a),        R^(10b) and R^(11a), R^(10a) and R^(11b) or R^(10b) and R^(11b)        together with the atoms to which they are attached form an aryl,        heteroaryl or heterocyclyl ring, optionally substituted with one        or more, in one embodiment, one to three, in another embodiment,        one, two or three groups selected from Q²; and the remainder of        R^(9a), R^(10a) and R^(11a) are each independently hydrogen,        deuterium or alkyl; and the remainder of R^(9b), R^(10b) and        R^(11b) are each independently hydrogen, deuterium, halo or        alkyl; or    -   iii) R^(9a) and R^(10b), R^(9b) and R^(10b), R^(9b) and R^(10a),        R^(10b) and R^(11a), R^(10a) and R^(11b) or R^(10b) and R^(11b)        together with the atoms to which they are attached form an aryl,        heteroaryl or heterocyclyl ring optionally fused to a phenyl        ring optionally substituted with one or more, in one embodiment,        one to three, in another embodiment, one, two or three groups        selected from Q²; and the remainder of R^(9a) and R^(9b) or the        remainder of R^(11a) and R^(11b) are each independently        hydrogen, deuterium or alkyl;

each Q² is independently halo, deuterium, cyano, oxo, thioxo, alkyl,haloalkyl, haloalkenyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl,—R^(u)OR^(x), —R^(u)OR^(u)OR^(x), —R^(u)OR^(u)N(R^(y))(R^(z)),—R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x), —R^(u)C(J)R^(x), —R^(u)C(J)OR^(x),—R^(u)C(J)N(R^(y))(R^(z)), —R^(u)C(J)R^(u)N(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —C(═NOR^(x))R^(x), —R^(u)S(O)_(t)R^(w),—R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w) or —C(═NR^(y))N(R^(y))OR^(x), where thealkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more groups Q⁴; in one embodiment, one to threeQ⁴ groups, each Q⁴ is independently selected from halo, deuterium,hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

R^(d) is hydrogen or alkyl;

each R^(u) is independently alkylene, alkenylene or a direct bond;

R^(w) is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl;

each R^(x) is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl;

R^(y) and R^(z) are each independently selected from (i) or (ii) below:

-   -   (i) R^(y) and R^(z) are each independently hydrogen, alkyl,        haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl,        cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl,        heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or        heteroaralkyl; or    -   (ii) R^(y) and R^(z), together with the nitrogen atom to which        they are attached, form a heterocyclyl or heteroaryl, optionally        substituted with one or more, in one embodiment, one, two or        three Q⁷ groups; each Q⁷ is independently selected from halo,        deuterium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl,        hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,        cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl,        heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2;

n is 1 or 2; and

q is an integer from 0-4,

wherein the compounds are selected such that: i) when W is CH; W¹ is C;Z is S; R¹ is hydrogen, or hydroxyl and R² is hydrogen, or R¹ and R²together form ═O; then ring A is not pyridine; ii) when W is CH; W¹ isN; Z is S; R¹ and R² are hydrogen, then ring A is not pyrrolidine; iii)when W is CH, Z is NH, R¹ and R² together form ═O, q is 0, and R⁴ ispyridinyl, then ring A is not phenyl, iv) when W is CH, Z is NH, R¹ andR² together form ═O, q is 0, and R⁴ is phenyl, then ring A is notpyrrolidine, and v) when Z is N, one of R¹ and R² is methyl and theother of R¹ and R² is H, q is 0, and R³ is pyridine, and W¹ is N, ring Acannot be piperidine, 1,2,3,4-tetrahydroisoquinoline, or isoindoline.

In certain embodiments, provided herein are compounds of Formula I orpharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof, wherein:

R¹ and R² are each independently selected from hydrogen, halogen,hydroxyl and alkoxy, or R¹ and R² together form ═O;

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl, whereR⁴ is optionally substituted with one or more, in one embodiment, one tothree, in another embodiment, one, two or three groups selected from Q¹;

each Q¹ is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl,aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w), ═NOR^(d), or —C(═NR^(y))N(R^(y))OR^(x),where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q³ groups, in one embodiment, one to threeQ³ groups; each Q³ is independently selected from halo, hydroxyl, alkyl,haloalkyl and hydroxyalkyl;

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S or NR⁷;

R⁷ is hydrogen or alkyl;

each W is independently CR⁸ or N;

R⁸ is hydrogen or alkyl;

ring A is aryl or heteroaryl, optionally substituted with one to foursubstituents selected from Q²;

W¹ is N or C;

W² is N, NR^(9a) or CR^(9b);

W³ is N, NR^(10a) or CR^(10b);

W⁴ is N, NR^(11a) or CR^(11b);

R^(9a), R^(9b), R^(10a), R^(10b), R^(11a) and R^(11b) are selected asfollows:

-   -   i) R^(9a), R^(10a) and R^(11a) are each independently hydrogen        or alkyl and R^(9b), R^(10b) and R^(11b) are each independently        hydrogen, oxo, hydroxyl, halo or alkyl; or    -   ii) R^(9a) and R^(10b), R^(9b) and R^(10b), R^(9b) and R^(10a),        R^(10b) and R^(11a), R^(10a) and R^(11b) or R^(10b) and R^(11b)        together with the atoms to which they are attached form an aryl        or heteroaryl ring, optionally substituted with one or more, in        one embodiment, one to three, in another embodiment, one, two or        three groups selected from Q²; and the remainder of R^(9a),        R^(10a) and R^(11a) are each independently hydrogen or alkyl;        and the remainder of R^(9b), R^(10b) and R^(11b) are each        independently hydrogen, halo or alkyl;

each Q² is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl,aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)SR,—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x),—R^(u)N(R^(x))C(J)OR^(x), —R^(u)N(R^(x))S(O)_(t)R^(w) or—C(═NR^(y))N(R^(y))OR^(x), where the alkyl, haloalkyl, aminoalkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, andheterocyclyl groups are optionally substituted with one or more groupsQ⁴; in one embodiment, one to three Q⁴ groups, each Q⁴ is independentlyselected from halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

R^(d) is hydrogen or alkyl;

each R^(u) is independently alkylene or a direct bond; R^(w) is alkyl,haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl,heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;

each R^(x) is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl;

R^(y) and R^(z) are each independently selected from (i) or (ii) below:

-   -   (i) R^(y) and R^(z) are each independently hydrogen, alkyl,        haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl,        cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl,        heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or        heteroaralkyl; or    -   (ii) R^(y) and R^(z), together with the nitrogen atom to which        they are attached, form a heterocyclyl or heteroaryl, optionally        substituted with one or more, in one embodiment, one, two or        three Q⁷ groups; each Q⁷ is independently selected from halo,        deuterium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl,        hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,        cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl,        heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2;

n is 1 or 2; and

q is an integer from 0-4,

wherein the compounds are selected such that when W is CH; W¹ is C; Z isS; R¹ is hydrogen, or hydroxyl and R² is hydrogen, or R¹ and R² togetherform ═O; then ring A is not pyridine.

In certain embodiments, provided herein are compounds of Formula Iwherein ring A is heteroaryl, n is 1 and the other variables are asdescribed elsewhere herein. In certain embodiments, provided herein arecompounds of Formula I wherein ring A is heteroaryl, W¹ is N, n is 1 or2 and the other variables are as described elsewhere herein. In certainembodiments, provided herein are compounds of Formula I wherein ring Ais heteroaryl, W¹ is C or N, n is 1 or 2, provided that when W¹ is C, nis 1 and the other variables are as described elsewhere herein.

In certain embodiments, provided herein are compounds of Formula I,wherein ring A is bicyclic or tricyclic heteroaryl, and the othervariables are as described elsewhere herein.

In certain embodiments, provided herein are compounds of Formula I orpharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof, wherein:

R¹ and R² are each independently selected from hydrogen, halogen,hydroxyl and alkoxy;

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl, whereR⁴ is optionally substituted with one or more, in one embodiment, one tothree, in another embodiment, one, two or three groups selected from Q¹;

each Q¹ is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl,cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x);

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S or NR⁷;

R⁷ is hydrogen or alkyl;

each W is independently CR⁸ or N;

R⁸ is hydrogen, haloalkyl or alkyl;

ring A is aryl or heteroaryl, optionally substituted with one to foursubstituents selected from Q²;

W¹ is N or C;

W² is N, NR^(9a) or CR^(9b);

W³ is N, NR^(10a) or CR^(10b);

W⁴ is N, NR^(11a) or CR^(11b);

R^(9a), R^(9b), R^(10a), R^(10b), R^(11a) and R^(11b) are selected asfollows:

-   -   i) R^(9a), R^(10a) and R^(11a) are each independently hydrogen        or alkyl and R^(9b), R^(10b) and R^(11b) are each independently        hydrogen, oxo, hydroxyl, halo or alkyl; or    -   ii) R^(9a) and R^(10b), R^(9a) and R^(10a), R^(9b) and R^(10b),        R^(9b) and R^(10a), R^(10a) and R^(11a), R^(10b) and R^(11a),        R^(10a) and R^(11b) or R^(10b) and R^(11b) together with the        atoms to which they are attached form an aryl, heteroaryl or        heterocyclyl ring, optionally substituted with one or more, in        one embodiment, one to three, in another embodiment, one, two or        three groups selected from Q²; and the remainder of R^(9a),        R^(10a) and R^(11a) are each independently hydrogen or alkyl;        and the remainder of R^(9b) R^(10b) and R^(11b) are each        independently hydrogen, halo or alkyl;

each Q² is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl,aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x),—R^(u)N(R^(x))C(J)OR^(x), —R^(u)N(R^(x))S(O)_(t)R^(w) or—C(═NR^(y))N(R^(y))OR^(x), where the alkyl, haloalkyl, aminoalkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, andheterocyclyl groups are optionally substituted with one or more Q⁴groups; in one embodiment, one to three Q⁴ groups, each Q⁴ isindependently selected from halo, hydroxyl, alkyl, haloalkyl andhydroxyalkyl;

each R^(u) is independently alkylene or a direct bond;

R^(w) is alkyl;

each R^(x) is independently hydrogen or alkyl;

R^(y) and R^(z) are each independently hydrogen or alkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2;

n is 1 or 2; and

q is an integer from 0-4,

wherein the compounds are selected such that when W is CH; W¹ is C; Z isS; R¹ is hydrogen, or hydroxyl and R² is hydrogen, or R¹ and R² togetherform ═O; then ring A is not pyridine.

In certain embodiments, the compounds of Formula I is selected such thatwhen W is CH; W¹ is C; Z is NH; R¹ and R² together form ═O; and q is 0,then ring A is not phenyl. In certain embodiments, the compounds ofFormula I is selected such that when i) W is CH; W¹ is C; Z is S; R¹ ishydrogen or hydroxyl and R² is hydrogen, or R¹ and R² together form ═O;then ring A is not pyridine and ii) when W is CH; W¹ is C; Z is NH; R¹and R² together form ═O; and q is 0, then ring A is not phenyl.

In certain embodiments, the compounds provided herein are selected suchthat when W is CH; W¹ is C; Z is S; R¹ is hydrogen, or hydroxyl and R²is hydrogen, or R¹ and R² together form ═O; then ring A is not a 6membered heteroaryl ring.

In certain embodiments, the compounds provided herein are selected suchthat when W is CH; W¹ is C; Z is S; R¹ is hydrogen, or hydroxyl and R²is hydrogen, or R¹ and R² together form ═O; then ring A is a fusedbicyclic ring.

In certain embodiments, the compounds provided herein are selected suchthat when W is CH; W¹ is N; Z is S; R¹ and R² are hydrogen, then ring Ais not pyrrolidine.

In certain embodiments, the compounds provided herein are selected suchthat when W is CH; W¹ is N; Z is S; R¹ and R² are hydrogen, then ring Ais not 5-membered heterocyclyl.

In certain embodiments, the compounds provided herein are selected suchthat when W is CH, Z is NH, R¹ and R² together form ═O, q is 0, and R⁴is pyridinyl, then ring A is not phenyl.

In certain embodiments, the compounds provided herein are selected suchthat when W is CH, Z is NH, R¹ and R² together form ═O, q is 0, and R⁴is nitrogen containing heteroaryl, then ring A is not phenyl.

In certain embodiments, the compounds provided herein are selected suchthat when W is CH, Z is NH, R¹ and R² together form ═O, q is 0, and R⁴is monocyclic heteroaryl, then ring A is not phenyl.

In certain embodiments, the compounds provided herein are selected suchthat when W is CH, Z is NH, R¹ and R² together form ═O, q is 0, and R⁴is phenyl, then ring A is not pyrrolidine.

In certain embodiments, the compounds provided herein are selected suchthat when W is CH, Z is NH, R¹ and R² together form ═O, q is 0, and R⁴is phenyl, then ring A is not nitrogen containing heterocyclyl.

In certain embodiments, the compounds provided herein are selected suchthat when Z is N, one of R¹ and R² is methyl and the other of R¹ and R²is H, q is 0, and R³ is pyridine, and W¹ is N, ring A cannot bepiperidine, 1,2,3,4-tetrahydroisoquinoline, or isoindoline.

In certain embodiments, the compounds provided herein are selected suchthat when Z is N, one of R¹ and R² is methyl and the other of R¹ and R²is H, q is 0, and R³ is pyridine, and W¹ is N, ring A cannot be nitrogencontaining heterocyclyl. In certain embodiments, the compounds providedherein are selected such that when Z is N, one of R¹ and R² is methyland the other of R¹ and R² is H, q is 0, and R³ is pyridine, and W¹ isN, ring A cannot be heterocyclyl.

In certain embodiments, provided herein are compounds of Formula I,wherein R¹ and R² are each independently selected from hydrogen andhalogen. In certain embodiments, R¹ and R² are each hydrogen. In certainembodiments, R¹ is hydrogen and R² is halogen. In certain embodiments,R¹ and R² are each halogen. In certain embodiments, R¹ and R² are eachindependently selected from hydrogen and fluorine. In certainembodiments, R¹ is alkoxy and R² is hydrogen. In certain embodiments, R¹is hydroxy and R² is hydrogen.

In certain embodiments, R³ is hydrogen or alkyl. In certain embodiments,R³ is hydrogen or methyl. In certain embodiments, R³ is hydrogen.

In certain embodiments, R⁴ is cycloalkyl, aryl, heterocyclyl orheteroaryl, where R⁴ is optionally substituted with one or more, in oneembodiment, one to three, in another embodiment, one, two or threegroups selected from Q¹; each Q¹ is independently halo, oxo, alkyl,haloalkyl, hydroxyalkyl, cycloalkyl, ═NOH, —R^(u)OR^(x) or—R^(u)C(O)R^(x), each R^(u) is independently alkylene or a direct bond;and each R^(x) is independently hydrogen or alkyl. In certainembodiments, R⁴ is cycloalkyl or heterocyclyl, where R⁴ is optionallysubstituted with one or more Q¹.

In certain embodiments, R⁴ is cyclohexyl, tetrahydrofuryl, pyridinyl,phenyl, morpholinyl, cyclopentyl, piperidinyl, tetrahydro-2H-pyranyl or2,3-dihydro-1H-indenyl, where R⁴ is optionally substituted with one ormore, in one embodiment, one to three, in another embodiment, one, twoor three groups selected from Q¹; each Q¹ is independently halo, oxo,alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, ═NOH, —R^(u)OR^(x) or—R^(u)C(O)R^(x), each R^(u) is independently alkylene or a direct bond;and each R^(x) is independently hydrogen or alkyl.

In certain embodiments, R⁴ is cycloalkyl, optionally substituted withone, two or three groups selected from Q¹; each Q¹ is independentlyhalo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, ═NOH,—R^(u)OR^(x) or —R^(u)C(O)R^(x), each R^(u) is independently alkylene ora direct bond; and each R^(x) is independently hydrogen or alkyl.

In certain embodiments, R⁴ is cyclohexyl, optionally substituted withhydroxyl.

In certain embodiments, Y is direct bond or —(CR⁵R⁶)_(q)—; R⁵ and R⁶ areeach independently hydrogen, halo, alkyl, haloalkyl or hydroxyalkyl. Incertain embodiments, Y is direct bond or —(CR⁵R⁶)_(q)—; R⁵ and R⁶ areeach independently hydrogen, alkyl or hydroxyalkyl. In certainembodiments, Y is direct bond, —CH₂—, —CH(CH₃)— or —CH(CH₂OH)—.

In certain embodiments, Z is O, S or NH. In certain embodiments, Z is Oor S.

In certain embodiments, each W is independently CR⁸ or N; and R⁸ ishydrogen, halo or alkyl. In certain embodiments, each W is CR⁸; and R⁸is hydrogen or alkyl. In certain embodiments, each W is CH.

In certain embodiments, ring A is aryl or heteroaryl, optionallysubstituted with one or two substituents selected from Q²; where Q² isheteroaryl, —R^(u)C(J)N(R^(y))(R^(z)), or —R^(u)N(R^(x))C(J)R^(x), wherewhen Q² is the heteroaryl, it is optionally substituted with one or morealkyl;

each R^(u) is independently alkylene or a direct bond;

each R^(x) is independently hydrogen or alkyl;

R^(y) and R^(z) are each independently hydrogen or alkyl; and

J is O, NR^(x) or S.

In certain embodiments, ring A is heteroaryl, optionally substitutedwith one or two substituents selected from Q²; where Q² is heteroaryl,—R^(u)C(J)N(R^(y))(R^(z)), or —R^(u)N(R^(x))C(J)R^(x), where when Q²heteroaryl, it is optionally substituted with one or more alkyl;

each R^(u) is independently alkylene or a direct bond;

each R^(x) is independently hydrogen or alkyl;

R^(y) and R^(z) are each independently hydrogen or alkyl; and

J is O, NR^(x) or S.

In certain embodiments, provided herein are compounds of Formula I:

or pharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof,wherein:

R¹ and R² are each independently selected from hydrogen, halogen,hydroxyl and alkoxy, or R¹ and R² together form ═O;

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl, whereR⁴ is optionally substituted with one or more, in one embodiment, one tothree, in another embodiment, one, two or three groups selected from Q¹;

each Q¹ is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl,aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w), ═NOR^(d), or —C(═NR^(y))N(R^(y))OR^(x),where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q³ groups, in one embodiment, one to threeQ³ groups; each Q³ is independently selected from halo, hydroxyl, alkyl,haloalkyl and hydroxyalkyl;

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S or NR⁷;

R⁷ is hydrogen or alkyl;

each W is independently CR⁸ or N;

R⁸ is hydrogen, halo, haloalkyl or alkyl;

ring A is a bicyclic or tricyclic heteroaryl or heterocyclyl optionallysubstituted with one to four substituents selected from Q²;

W¹ is N or C;

W² is N, NR^(9a) or CR^(9b);

W³ is N, NR^(10a) or CR^(10b);

W⁴ is N, NR^(11a) or CR^(11b); R^(9a), R^(9b), R^(10a), Rlb, R^(11a) andR^(11b) are selected as follows:

-   -   i) R^(9a) and R^(10b), R^(9a) and R^(10a), R^(9b) and R^(10b),        R^(9b) and R^(10a), R^(10a) and R^(11a), R^(10b) and R^(11a),        R^(10a) and R^(11b) or R^(10b) and R^(11b) together with the        atoms to which they are attached form an aryl, heteroaryl or        heterocyclyl ring, optionally substituted with one or more, in        one embodiment, one to three, in another embodiment, one, two or        three groups selected from Q²; and the remainder of R^(9a),        R^(10a) and R^(11a) are each independently hydrogen or alkyl;        and the remainder of R^(9b), R^(10b) and R^(11b) are each        independently hydrogen, halo or alkyl; or    -   ii) R^(9a) and R^(10b), R^(9a) and R^(10a), R^(9b) and R^(10b),        R^(9b) and R^(10a), R^(10a) and R^(11a), R^(10b) and R^(11a),        R^(10a) and R^(11b) or R^(10b) and R^(11b) together with the        atoms to which they are attached form an aryl, heteroaryl or        heterocyclyl ring optionally fused to a phenyl ring optionally        substituted with one or more, in one embodiment, one to three,        in another embodiment, one, two or three groups selected from        Q²; and the remainder of R^(9a) and R^(9b) or the remainder of        R^(11a) and R^(11b) are each independently hydrogen or alkyl;

each Q² is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl,haloalkenyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)OR^(x), —R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)),—R^(u)SR^(x), —R^(u)C(J)R^(x), —R^(u)C(J)OR^(x),—R^(u)C(J)N(R^(y))(R^(z)), —R^(u)C(J)R^(u)N(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —C(═NOR^(x))R^(x), —R^(u)S(O)_(t)R^(w),—R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w) or —C(═NR^(y))N(R^(y))OR^(x), where thealkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more groups Q⁴; in one embodiment, one to threeQ⁴ groups, each Q⁴ is independently selected from halo, hydroxyl, alkyl,haloalkyl and hydroxyalkyl;

R^(d) is hydrogen or alkyl;

each R^(u) is independently alkylene, alkenylene or a direct bond;

R^(w) is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl;

each R^(x) is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl;

R^(y) and R^(z) are each independently selected from (i) or (ii) below:

(i) R^(y) and R^(z) are each independently hydrogen, alkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl; or

(ii) R^(y) and R^(z), together with the nitrogen atom to which they areattached, form a heterocyclyl or heteroaryl, optionally substituted withone or more, in one embodiment, one, two or three Q⁷ groups; each Q⁷ isindependently selected from halo, deuterium, oxo, thioxo, hydroxy,alkoxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl,aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2;

n is 1 or 2; and

q is an integer from 0-4,

wherein the compound is selected such that when Z is N, one of R¹ and R²is methyl and the other of R¹ and R² is H, q is 0, and R³ is pyridine,and W¹ is N, ring A cannot be 1,2,3,4-tetrahydroisoquinoline, orisoindoline

In certain embodiments, W¹ is N. In certain embodiments, W¹ is C.

In certain embodiments, W² is N or CR^(9b), where R^(9b) is hydrogenoxo, hydroxyl or alkyl. In certain embodiments, W³ is N or CR^(10b),where R^(10b) is hydrogen or alkyl. In certain embodiments, W⁴ is N orCR^(11b), where R^(11b) is hydrogen or alkyl. In certain embodiments, W²is CR^(9b); W³ is CR^(10b); W⁴ is N or CR^(11b); where R^(9b) andR^(10b) together with the carbon atoms on which they are substitutedform an aryl or heteroaryl ring, optionally substituted with one ormore, in one embodiment, one to three, in another embodiment, one, twoor three groups selected from Q²; R^(11b) is hydrogen or alkyl;

each Q² is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl,aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x),—R^(u)N(R^(x))C(J)OR^(x), —R^(u)N(R^(x))S(O)_(t)R^(w) or—C(═NR^(y))N(R^(y))OR^(x), where the alkyl, haloalkyl, aminoalkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, andheterocyclyl groups are optionally substituted with one or more Q⁴groups; each Q⁴ is independently selected from halo, hydroxyl, alkyl,haloalkyl and hydroxyalkyl;

each R^(u) is independently alkylene or a direct bond;

R^(w) is alkyl;

each R^(x) is independently hydrogen or alkyl;

R^(y) and R^(z) are each independently hydrogen or alkyl;

J is O, NR^(x) or S; and

each t is independently an integer from 0-2.

In certain embodiments, W² is CR^(9b); W³ is CR^(10b); W⁴ is N; whereR^(9b) and R^(10b) together with the carbon atoms on which they aresubstituted form an aryl or heteroaryl ring, optionally substituted withone or two groups selected from Q², where Q² is as defined elsewhereherein. In certain embodiments, each Q² is independently halo, cyano,alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl,heterocyclyl, —R^(u)OR^(x), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x),—R^(u)N(R^(x))C(J)OR^(x), —R^(u)N(R^(x))S(O)_(t)R^(w) or—C(═NR^(y))N(R^(y))OR^(x), where the alkyl, haloalkyl, aminoalkyl,alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocyclyl groups areoptionally substituted with one or more Q⁴ groups; each Q⁴ isindependently selected from halo, hydroxyl, alkyl, haloalkyl andhydroxyalkyl;

each R^(u) is independently alkylene or a direct bond;

R^(w) is alkyl;

each R^(x) is independently hydrogen or alkyl;

R^(y) and R^(z) are each independently hydrogen or alkyl;

J is O, NR^(x) or S; and

each t is independently an integer from 0-2.

In certain embodiments, n is 1 or 2. In certain embodiments, n is 1. Incertain embodiments, n is 2.

In certain embodiments, q is an integer from 0-4. In certainembodiments, q is 0-3. In certain embodiments, q is 0-2. In certainembodiments, q is 0, 1 or 2. In certain embodiments, q is 0. In certainembodiments, q is 1. In certain embodiments, q is 2.

In certain embodiments, provided herein are compounds of Formula I orpharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof, wherein:

R¹ and R² are each independently selected from hydrogen, alkoxy andhalogen;

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, aryl, heterocyclyl or heteroaryl, where R⁴ isoptionally substituted with one or more, in one embodiment, one tothree, in another embodiment, one, two or three groups selected from Q¹;

each Q¹ is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl,cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x);

Y is direct bond or —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NR⁷;

R⁷ is hydrogen or alkyl;

each W is independently CR⁸ or N;

R⁸ is hydrogen, haloalkyl or alkyl;

ring A is aryl or heteroaryl;

W¹ is N or C;

W² is N, NR^(9a) or CR^(9b);

W³ is N, NR^(10a) or CR^(10b);

W⁴ is N, NR^(11a) or CR^(11b);

R^(9a), R^(9b), R^(10a), R^(10b), R^(11a) and R^(11b) are selected asfollows:

-   -   i) R^(9a), R^(10a) and R^(11a) are each independently hydrogen        or alkyl; and R^(9b), R^(10b) and R^(11b) are each independently        hydrogen, oxo, hydroxyl, halo or alkyl; or    -   ii) R^(9a) and R^(10b), R^(9a) and R^(10a), R^(9b) and R^(10b),        R^(9b) and R^(10a), R^(10a) and R^(11a), R^(10b) and R^(11a),        R^(10a) and R^(11b) or R^(10b) and R^(11b) together with the        atoms to which they are attached form an aryl or heteroaryl        ring, optionally substituted with one or more, in one        embodiment, one to three, in another embodiment, one, two or        three groups selected from Q²; the remainder of R^(9a), R^(10a)        and R^(11a) are each independently hydrogen or alkyl; the        remainder of R^(9b) R^(10b) and R^(11b) are each independently        hydrogen, halo or alkyl;

each Q² is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl,aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x),—R^(u)N(R^(x))C(J)OR^(x), —R^(u)N(R^(x))S(O)_(t)R^(w) or—C(═NR^(y))N(R^(y))OR^(x), where the alkyl, haloalkyl, aminoalkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, andheterocyclyl groups are optionally substituted with one or more Q⁴groups; each Q⁴ is independently selected from halo, hydroxyl, alkyl,haloalkyl and hydroxyalkyl;

each R^(u) is independently alkylene or a direct bond;

R^(w) is alkyl;

each R^(x) is independently hydrogen or alkyl;

R^(y) and R^(z) are each independently hydrogen or alkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2;

n is 1; and

q is an integer from 0-2.

In certain embodiments, provided herein are compounds of Formula II

or pharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof,wherein:

R¹ and R² are each independently selected from hydrogen, alkoxy andhalogen;

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl, whereR⁴ is optionally substituted with one or more, in one embodiment, one tothree, in another embodiment, one, two or three groups selected from Q¹;

each Q¹ is independently deuterium, halo, cyano, oxo, thioxo, alkyl,haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w), ═NOR^(d), or —C(═NR^(y))N(R^(y))OR^(x),where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q³ groups, in one embodiment, one to threeQ³ groups; each Q³ is independently selected from deuterium, halo,hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NR⁷;

R⁷ is hydrogen or alkyl;

each W is independently CR⁸ or N;

R⁸ is hydrogen, haloalkyl or alkyl;

ring A is aryl or heteroaryl, optionally substituted with one to foursubstituents selected from Q²;

W¹ is N or C;

W² is N, NR^(9a) or CR^(9b);

W³ is N, NR^(10a) or CR^(10b);

W⁴ is N, NR^(11a) or CR^(11b);

R^(9a), R^(9b), R^(10a), R^(10b), R^(11a) and R^(11b) are selected asfollows:

-   -   i) R^(9a), R^(10a) and R^(11a) are each independently hydrogen        or alkyl and R^(9b), R^(10b) and R^(11b) are each independently        hydrogen or Q²; or    -   ii) R^(9a) and R^(10b), R^(9a) and R^(10a), R^(9b) and R^(10b),        R^(9b) and R^(10a), R^(10a) and R^(11a), R^(10b) and R^(11a),        R^(10a) and R^(11b) or R^(10b) and R^(11b) together with the        atoms to which they are attached form an aryl or heteroaryl        ring, optionally substituted with one or more, in one        embodiment, one to three, in another embodiment, one, two or        three groups selected from Q²; the remainder of R^(9a) or        R^(11a) is hydrogen or alkyl; and the remainder of R^(9b) or        R^(11b) is independently hydrogen or Q²;

each Q² is independently halo, deuterium, cyano, oxo, thioxo, alkyl,haloalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl,—R^(u)OR^(x), —R^(u)OR^(u)OR^(x), —R^(u)OR^(u)N(R^(y))(R^(z)),—R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x), —R^(u)C(J)R^(x), —R^(u)C(J)OR^(x),—R^(u)C(J)N(R^(y))(R^(z)), —R^(u)C(J)R^(u)N(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —C(═NOR^(x))R^(x), —R^(u)S(O)_(t)R^(w),—R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w) or —C(═NR^(y))N(R^(y))OR^(x), where thealkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q⁴ groups; each Q⁴ is independentlyselected from halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

each R^(d) is independently hydrogen or alkyl;

each R^(u) is independently alkylene, alkenylene or a direct bond;

R^(w) is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl;

each R^(x) is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl;

R^(y) and R^(z) are each independently selected from (i) or (ii) below:

-   -   (i) R^(y) and R^(z) are each independently hydrogen, alkyl,        haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl,        cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl,        heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or        heteroaralkyl; or    -   (ii) R^(y) and R^(z), together with the nitrogen atom to which        they are attached, form a heterocyclyl or heteroaryl, optionally        substituted with one or more, in one embodiment, one, two or        three Q⁷ groups; each Q⁷ is independently selected from halo,        deuterium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl,        hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,        cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl,        heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2; and

q is an integer from 0-2;

wherein the compounds are selected such that when i) W is CH; W¹ is C; Zis S; R¹ is hydrogen, or hydroxyl and R² is hydrogen, or R¹ and R²together form ═O; then ring A is not pyridine and ii) when W is CH; W¹is C; Z is NH; R¹ and R² together form ═O; and q is 0, then ring A isnot phenyl.

In certain embodiments, provided herein are compounds of Formula IIwherein each Q¹ is independently halo, oxo, alkyl, haloalkyl,hydroxyalkyl, cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x); eachR^(u) is independently alkylene or a direct bond; each R^(x) isindependently hydrogen or alkyl; and the other variables are asdescribed elsewhere herein. In certain embodiments, provided herein arecompounds of Formula II wherein ring A is heteroaryl optionallysubstituted with one to four substituents selected from Q²; n is 1 andthe other variables are as described elsewhere herein.

In certain embodiments, provided herein are compounds of Formula II

or pharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof,wherein:

R¹ and R² are each independently selected from hydrogen, alkoxy andhalogen;

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl, whereR⁴ is optionally substituted with one or more, in one embodiment, one tothree, in another embodiment, one, two or three groups selected from Q¹;

each Q¹ is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl,cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x);

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NR⁷;

R⁷ is hydrogen or alkyl;

each W is independently CR⁸ or N;

R⁸ is hydrogen, halo, haloalkyl or alkyl;

ring A is aryl or heteroaryl, optionally substituted with one to foursubstituents selected from Q²;

W¹ is N or C;

W² is N, NR^(9a) or CR^(9b);

W³ is N, NR^(10a) or CR^(10b);

W⁴ is N, NR^(11a) or CR^(11b);

R^(9a), R^(9b), R^(10a), R^(10b), R^(11a) and R^(11b) are selected asfollows:

-   -   i) R^(9a), R^(10a) and R^(11a) are each independently hydrogen        or alkyl and R^(9b), R^(10b) and R^(11b) are each independently        hydrogen, oxo, hydroxyl, halo or alkyl; or    -   ii) R^(9a) and R^(10b), R^(9a) and R^(10a), R^(9b) and R^(10b),        R^(9b) and R^(10a), R^(10a) and R^(11a), R^(10b) and R^(11a),        R^(10a) and R^(11b) or R^(10b) and R^(11b) together with the        atoms to which they are attached form an aryl or heteroaryl        ring, optionally substituted with one or more, in one        embodiment, one to three, in another embodiment, one, two or        three groups selected from Q²; the remainder of R^(9a), R^(10a)        and R^(11a) are each independently hydrogen or alkyl; the        remainder of R^(9b) R^(10b) and R^(11b) are each independently        hydrogen, halo or alkyl;

each Q² is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl,aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x),—R^(u)N(R^(x))C(J)OR^(x), —R^(u)N(R^(x))S(O)_(t)R^(w) or—C(═NR^(y))N(R^(y))OR^(x), where the alkyl, haloalkyl, aminoalkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, andheterocyclyl groups are optionally substituted with one or more Q⁴groups; each Q⁴ is independently selected from halo, hydroxyl, alkyl,haloalkyl and hydroxyalkyl;

each R^(u) is independently alkylene or a direct bond;

R^(w) is alkyl;

each R^(x) is independently hydrogen or alkyl;

R^(y) and R^(z) are each independently hydrogen or alkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2; and

q is an integer from 0-2.

In certain embodiments, provided herein are compounds of Formula IIwherein ring A is heteroaryl optionally substituted with one to foursubstituents selected from Q² and the other variables are as describedelsewhere herein.

In certain embodiments, compound of formula II us selected such that: i)when W is CH; W¹ is N; Z is S; R¹ and R² are hydrogen, then ring A isnot pyrrolidine; ii) when W is CH, Z is NH, R¹ and R² together form ═O,q is 0, and R⁴ is phenyl, then ring A is not pyrrolidine, and iii) whenZ is N, one of R¹ and R² is methyl and the other of R¹ and R² is H, q is0, and R³ is pyridine, and W¹ is N, ring A cannot be isoindoline.

In certain embodiments, provided herein are compounds of Formula II,wherein ring A is bicyclic or tricyclic heteroaryl, and the othervariables are as described elsewhere herein.

In certain embodiments, provided herein are compounds of Formula II orpharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof, wherein:

R¹ and R² are each independently selected from hydrogen, alkoxy andhalogen;

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl, whereR⁴ is optionally substituted with one or more, in one embodiment, one tothree, in another embodiment, one, two or three groups selected from Q¹;

each Q¹ is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl,cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x);

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NR⁷;

R⁷ is hydrogen or alkyl;

each W is independently CR⁸ or N;

R⁸ is hydrogen, halo, haloalkyl or alkyl;

ring A is heteroaryl or heterocyclyl, optionally substituted with one tofour substituents selected from Q²;

W¹ is N or C;

W² is N, NR^(9a) or CR^(9b);

W³ is N, NR^(10a) or CR^(10b);

W⁴ is N, NR^(11a) or CR^(11b);

R^(9a), R^(9b), R^(10a), R^(10b), R^(11a) and R^(11b) are selected asfollows:

-   -   i) R^(9a), R^(10a) and R^(11a) are each independently hydrogen        or alkyl and R^(9b), R^(10b) and R^(11b) are each independently        hydrogen, oxo, hydroxyl, halo or alkyl; or    -   ii) R^(9a) and R^(10b), R^(9a) and R^(10a), R^(9b) and R^(10b),        R^(9b) and R^(10a), R^(10a) and R^(11a), R^(10b) and R^(11a),        R^(10a) and R^(11b) or R^(10b) and R^(11b) together with the        atoms to which they are attached form an aryl, heteroaryl or        heterocyclyl ring, optionally substituted with one or more, in        one embodiment, one to three, in another embodiment, one, two or        three groups selected from Q²; the remainder of R^(9a), R^(10a)        and R^(11a) are each independently hydrogen or alkyl; the        remainder of R^(9b) R^(10b) and R^(11b) are each independently        hydrogen, halo or alkyl; or    -   iii) R^(9a) and R^(10b), R^(9a) and R^(10a), R^(9b) and R^(10b),        R^(9b) and R^(10a), R^(10a) and R^(11a), R^(10b) and R^(11a),        R^(10a) and R^(11b) or R^(10b) and R^(11b) together with the        atoms to which they are attached form an aryl, heteroaryl or        heterocyclyl ring optionally fused to a phenyl ring optionally        substituted with one or more, in one embodiment, one to three,        in another embodiment, one, two or three groups selected from        Q²; and the remainder of R^(9a) and R^(9b) or the remainder of        R^(11a) and R^(11b) are each independently hydrogen or alkyl;

each Q² is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl,aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x), —R^(u)OR^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)C(J)R^(u)N(R^(y))(R^(z)), —R^(u)C(J)N(R^(y))OR^(x),—C(═NOR^(x))R^(x), —R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x),—R^(u)N(R^(x))C(J)OR^(x), —R^(u)N(R^(x))S(O)_(t)R^(w) or—C(═NR^(y))N(R^(y))OR^(x), where the alkyl, haloalkyl, aminoalkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, andheterocyclyl groups are optionally substituted with one or more Q⁴groups; each Q⁴ is independently selected from halo, hydroxyl, alkyl,haloalkyl and hydroxyalkyl;

each R^(u) is independently alkylene, alkenylene or a direct bond;

R^(w) is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl;

each R^(x) is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl;

R^(y) and R^(z) are each independently selected from (i) or (ii) below:

(i) R^(y) and R^(z) are each independently hydrogen, alkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl; or

(ii) R^(y) and R^(z), together with the nitrogen atom to which they areattached, form a heterocyclyl or heteroaryl, optionally substituted withone or more, in one embodiment, one, two or three Q⁷ groups; each Q⁷ isindependently selected from halo, deuterium, oxo, thioxo, hydroxy,alkoxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl,aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2; and

q is an integer from 0-2;

wherein the compounds are selected such that when W is CH; W¹ is N; Z isS; R¹ and R² are hydrogen, then ring A is not pyrrolidine.

In certain embodiments, provided herein are compounds of Formula II orpharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof,

wherein:

R¹ and R² are each independently selected from hydrogen, alkoxy andhalogen;

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl, whereR⁴ is optionally substituted with one or more, in one embodiment, one tothree, in another embodiment, one, two or three groups selected from Q¹;

each Q¹ is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl,cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x);

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NR⁷;

R⁷ is hydrogen or alkyl;

each W is independently CR⁸ or N;

R⁸ is hydrogen, halo, haloalkyl or alkyl;

ring A is bicyclic heteroaryl or heterocyclyl, optionally substitutedwith one to four substituents selected from Q²;

W¹ is N or C;

W² is N, NR^(9a) or CR^(9b);

W³ is CR^(10b);

W⁴ is N;

R^(9a), R^(9b), and R^(10b) are selected as follows:

R^(9a) and R^(10b) or R^(9b) and R^(10b), together with the atoms towhich they are attached, form an aryl, heteroaryl or heterocyclyl ring,optionally substituted with one or more, in one embodiment, one tothree, in another embodiment, one, two or three groups selected from Q²;the remainder of R^(9a) and R^(10b) is hydrogen or alkyl;

each Q² is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl,aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x), —R^(u)OR^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)C(J)R^(u)N(R^(y))(R^(z)), —R^(u)C(J)N(R^(y))OR^(x),—C(═NOR^(x))R^(x), —R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x),—R^(u)N(R^(x))C(J)OR^(x), —R^(u)N(R^(x))S(O)_(t)R^(w) or—C(═NR^(y))N(R^(y))OR^(x), where the alkyl, haloalkyl, aminoalkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, andheterocyclyl groups are optionally substituted with one or more Q⁴groups; each Q⁴ is independently selected from halo, hydroxyl, alkyl,haloalkyl and hydroxyalkyl;

each R^(u) is independently alkylene, alkenylene or a direct bond;

R^(w) is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl;

each R^(x) is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl;

R^(y) and R^(z) are each independently selected from (i) or (ii) below:

-   -   (i) R^(y) and R^(z) are each independently hydrogen, alkyl,        haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl,        cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl,        heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or        heteroaralkyl; or    -   (ii) R^(y) and R^(z), together with the nitrogen atom to which        they are attached, form a heterocyclyl or heteroaryl, optionally        substituted with one or more, in one embodiment, one, two or        three Q⁷ groups; each Q⁷ is independently selected from halo,        deuterium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl,        hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,        cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl,        heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2; and

q is an integer from 0-2.

In certain embodiments, provided herein are compounds of Formula IIwherein W⁴ is N; W² is N, NR^(9a) or CR^(9b); W³ is CR^(10b); and R^(9a)and R^(10b) or R^(9b) and R^(10b), together with the atoms to which theyare attached, form an aryl, heteroaryl or heterocyclyl ring, optionallysubstituted with one or more, in one embodiment, one to three, inanother embodiment, one, two or three groups selected from Q² and theother variables are as described elsewhere herein.

In certain embodiments, provided herein are compounds of Formula IIwherein R⁴ is cycloalkyl, optionally substituted with one or more, inone embodiment, one to three, in another embodiment, one, two or threegroups selected from Q¹; each Q¹ is independently halo, oxo, alkyl,haloalkyl, hydroxyalkyl, cycloalkyl, ═NOH, —R^(u)OR^(x) or—R^(u)C(O)R^(x); Y is —(CR⁵R⁶)_(q)—;

each R^(u) is independently alkylene, alkenylene or a direct bond;

each R^(x) is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl; and

q is 0; and the other variables are as described elsewhere herein.

In certain embodiments, provided herein are compounds of Formula III

or pharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof,wherein:

R¹ and R² are each independently selected from hydrogen, halogen, alkoxyand hydroxyl;

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, aryl, heterocyclyl or heteroaryl, where R⁴ isoptionally substituted with one or more, in one embodiment, one tothree, in another embodiment, one, two or three groups selected from Q¹;

each Q¹ is independently deuterium, halo, cyano, oxo, thioxo, alkyl,haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w), ═NOR^(d), or —C(═NR^(y))N(R^(y))OR^(x),where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q³ groups, in one embodiment, one to threeQ³ groups; each Q³ is independently selected from deuterium, halo,hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S or NH;

each W is independently CR⁸ or N;

R⁸ is hydrogen, halo, haloalkyl or alkyl;

ring A is heteroaryl or heterocyclyl, optionally substituted with one tofour substituents selected from Q²;

W² is N or CR^(9b);

W³ is N or CR^(10b);

W⁴ is N or CR^(11b);

R^(9b), R^(10b) and R^(11b) are selected as follows:

-   -   i) R^(9b), R^(10b) and R^(11b) are each independently hydrogen        or Q²; or    -   ii) R^(9b) and R^(10b) or R^(10b) and R^(11b) together with the        atoms to which they are attached form an aryl or heteroaryl        ring, optionally substituted with one or more, in one        embodiment, one to three, in another embodiment, one, two or        three groups selected from Q²; and the remainder of R^(9b),        R^(10b) and R^(11b) is hydrogen or Q²;

each Q² is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl,aminoalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)OR^(x), —R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)),—R^(u)SR^(x), —R^(u)C(J)R^(x), —R^(u)C(J)OR^(x),—R^(u)C(J)N(R^(y))(R^(z)), —R^(u)C(J)R^(u)N(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —C(═NOR^(x))R^(x), —R^(u)S(O)_(t)R^(w),—R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w) or —C(═NR^(y))N(R^(y))OR^(x), where thealkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q⁴ groups; each Q⁴ is independentlyselected from halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

R^(d) is hydrogen or alkyl;

each R^(u) is independently alkylene, alkenylene or a direct bond;

R^(w) is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl;

each R^(x) is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl;

R^(y) and R^(z) are each independently selected from (i) or (ii) below:

-   -   (i) R^(y) and R^(z) are each independently hydrogen, alkyl,        haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl,        cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl,        heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or        heteroaralkyl; or    -   (ii) R^(y) and R^(z), together with the nitrogen atom to which        they are attached, form a heterocyclyl or heteroaryl, optionally        substituted with one or more, in one embodiment, one, two or        three Q⁷ groups; each Q⁷ is independently selected from halo,        deuterium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl,        hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,        cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl,        heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2;

n is 1 or 2; and

q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula IIIwherein each Q¹ is independently halo, oxo, alkyl, haloalkyl,hydroxyalkyl, cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x); eachR^(u) is independently alkylene or a direct bond; each R^(x) isindependently hydrogen or alkyl; and the other variables are asdescribed elsewhere herein.

In certain embodiments, provided herein are compounds of Formula III

or pharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof,wherein:

R¹ and R² are each independently selected from hydrogen, halogen, alkoxyand hydroxyl;

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, aryl, heterocyclyl or heteroaryl, where R⁴ isoptionally substituted with one or more, in one embodiment, one tothree, in another embodiment, one, two or three groups selected from Q¹;

each Q¹ is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl,cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x);

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S or NH;

each W is independently CR⁸ or N;

R⁸ is hydrogen, halo, haloalkyl or alkyl;

ring A is heteroaryl, optionally substituted with one to foursubstituents selected from Q²;

W² is N or CR^(9b);

W³ is N or CR^(10b);

W⁴ is N or CR^(11b);

R^(9b), R^(10b) and R^(11b) are selected as follows:

-   -   i) R^(9b), R^(10b) and R^(11b) are each independently hydrogen,        oxo, hydroxyl, halo or alkyl; or    -   ii) R^(9b) and R^(10b) or R^(10b) and R^(11b) together with the        atoms to which they are attached form an aryl or heteroaryl        ring, optionally substituted with one or more, in one        embodiment, one to three, in another embodiment, one, two or        three groups selected from Q²; and the remainder of R^(9b),        R^(10b) and R^(11b) is hydrogen, halo or alkyl;

each Q² is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl,aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x),—R^(u)N(R^(x))C(J)OR^(x), —R^(u)N(R^(x))S(O)_(t)R^(w) or—C(═NR^(y))N(R^(y))OR^(x), where the alkyl, haloalkyl, aminoalkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, andheterocyclyl groups are optionally substituted with one or more Q⁴groups; each Q⁴ is independently selected from halo, hydroxyl, alkyl,haloalkyl and hydroxyalkyl;

each R^(u) is independently alkylene or a direct bond;

R^(w) is alkyl;

each R^(x) is independently hydrogen or alkyl;

R^(y) and R^(z) are each independently hydrogen or alkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2;

n is 1 or 2; and

q is an integer from 0-4.

In certain embodiments, compound of Formula III is selected such that:i) when W is CH; Z is S; R¹ and R² are hydrogen, then ring A is notpyrrolidine; ii) when W is CH, Z is NH, R¹ and R² together form ═O, q is0, and R⁴ is phenyl, then ring A is not pyrrolidine; and iii) when Z isNH, one of R¹ and R² is methyl and the other of R¹ and R² is H, q is 0,and R³ is pyridine, and W¹ is N, ring A cannot be A cannot bepiperidine, 1,2,3,4-tetrahydroisoquinoline, or isoindoline.

In certain embodiments, provided herein are compounds of Formula IIIwherein ring A is heteroaryl and the other variables are as describedelsewhere herein. In certain embodiments, provided herein are compoundsof Formula III, wherein ring A is bicyclic or tricyclic heteroaryl, andthe other variables are as described elsewhere herein.

In certain embodiments, provided herein are compounds of Formula III orpharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof,

wherein

R¹ and R² are each independently selected from hydrogen or halogen;

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, optionally substituted with one or more, in oneembodiment, one to three, in another embodiment, one, two or threegroups selected from Q¹;

each Q¹ is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl,cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x);

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NH;

each W is independently CR⁸ or N;

R⁸ is hydrogen, halo, haloalkyl or alkyl;

ring A is heteroaryl optionally substituted with one to foursubstituents selected from Q²;

W² is N or CR^(9b);

W³ is N or CR^(10b);

W⁴ is N or CR^(11b);

R^(9b), R^(10b) and R^(11b) are selected as follows:

-   -   i) R^(9b), R^(10b) and R^(11b) are each independently hydrogen        or Q²; or    -   ii) R^(9b) and R^(10b) or R^(11b) and R^(11b), together with the        atoms to which they are attached, form an aryl or heteroaryl        ring, optionally substituted with one or more, in one        embodiment, one to three, in another embodiment, one, two or        three groups selected from Q²; and the remainder of R^(9b),        R^(10b) and R^(11b) is hydrogen or Q²;

each Q² is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl,aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x),—R^(u)N(R^(x))C(J)OR^(x), —R^(u)N(R^(x))S(O)_(t)R^(w) or—C(═NR^(y))N(R^(y))OR^(x), where the alkyl, haloalkyl, aminoalkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, andheterocyclyl groups are optionally substituted with one or more Q⁴groups; each Q⁴ is independently selected from halo, hydroxyl, alkyl,haloalkyl and hydroxyalkyl;

each R^(u) is independently alkylene or a direct bond;

R^(w) is alkyl;

each R^(x) is independently hydrogen or alkyl;

R^(y) and R^(z) are each independently hydrogen or alkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2;

n is 1 or 2; and

q is an integer from 0-2.

In certain embodiments, provided herein are compounds of Formula III orpharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof, wherein

R¹ and R² are each independently selected from hydrogen or halogen;

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, optionally substituted with one or more, in oneembodiment, one to three, in another embodiment, one, two or threegroups selected from Q¹;

each Q¹ is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl,cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x);

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NH;

each W is independently CR⁸ or N;

R⁸ is hydrogen, halo, haloalkyl or alkyl;

ring A is heteroaryl optionally substituted with one to foursubstituents selected from Q²;

W² is N or CR^(9b);

W³ is N or CR^(10b);

W⁴ is N or CR^(11b);

R^(9b), R^(10b) and R^(11b) are selected as follows:

-   -   i) R^(9b), R^(10b) and R^(11b) are each independently hydrogen,        oxo, hydroxyl, halo or alkyl; or    -   ii) R^(9b) and R^(10b) or R^(10b) and R^(11b), together with the        atoms to which they are attached, form an aryl or heteroaryl        ring, optionally substituted with one or more, in one        embodiment, one to three, in another embodiment, one, two or        three groups selected from Q²; and the remainder of R^(9b),        R^(10b) and R^(11b) is hydrogen, halo or alkyl;

each Q² is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl,aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x),—R^(u)N(R^(x))C(J)OR^(x), —R^(u)N(R^(x))S(O)_(t)R^(w) or—C(═NR^(y))N(R^(y))OR^(x), where the alkyl, haloalkyl, aminoalkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, andheterocyclyl groups are optionally substituted with one or more Q⁴groups; each Q⁴ is independently selected from halo, hydroxyl, alkyl,haloalkyl and hydroxyalkyl;

each R^(u) is independently alkylene or a direct bond;

R^(w) is alkyl;

each R^(x) is independently hydrogen or alkyl;

R^(y) and R^(z) are each independently hydrogen or alkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2;

n is 1 or 2; and

q is an integer from 0-2.

In certain embodiments, provided herein are compounds of Formula III orpharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof,

wherein:

R¹ and R² are each independently selected from hydrogen, halogen, alkoxyand hydroxyl;

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, aryl, heterocyclyl or heteroaryl, where R⁴ isoptionally substituted with one or more, in one embodiment, one tothree, in another embodiment, one, two or three groups selected from Q¹;

each Q¹ is independently deuterium, halo, cyano, oxo, thioxo, alkyl,haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w), ═NOR^(d), or —C(═NR^(y))N(R^(y))OR^(x),where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q³ groups, in one embodiment, one to threeQ³ groups; each Q³ is independently selected from deuterium, halo,hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S or NH;

each W is independently CR⁸ or N;

R⁸ is hydrogen, halo, haloalkyl or alkyl;

ring A is heteroaryl optionally substituted with one to foursubstituents selected from Q²;

W² is N or CR^(9b);

W³ is N or CR^(10b);

W⁴ is N or CR^(11b);

R^(9b), R^(10b) and R^(11b) are selected as follows:

-   -   i) R^(9b), R^(10b) and R^(11b) are each independently hydrogen,        or Q²; or    -   ii) R^(9b) and R^(10b) or R^(10b) and R^(11b) together with the        atoms to which they are attached form an aryl or heteroaryl        ring, optionally substituted with one or more, in one        embodiment, one to three, in another embodiment, one, two or        three groups selected from Q²; and the remainder of R^(9b),        R^(10b) and R^(11b) is hydrogen or Q²;

each Q² is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl,aminoalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)OR^(x), —R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)),—R^(u)SR^(x), —R^(u)C(J)R^(x), —R^(u)C(J)OR^(x),—R^(u)C(J)N(R^(y))(R^(z)), —R^(u)C(J)R^(u)N(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —C(═NOR^(x))R^(x), —R^(u)S(O)_(t)R^(w),—R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w) or —C(═NR^(y))N(R^(y))OR^(x), where thealkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q⁴ groups; each Q⁴ is independentlyselected from halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

R^(d) is hydrogen or alkyl;

each R^(u) is independently alkylene, alkenylene or a direct bond;

R^(w) is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl;

each R^(x) is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl;

R^(y) and R^(z) are each independently selected from (i) or (ii) below:

-   -   (i) R^(y) and R^(z) are each independently hydrogen, alkyl,        haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl,        cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl,        heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or        heteroaralkyl; or    -   (ii) R^(y) and R^(z), together with the nitrogen atom to which        they are attached, form a heterocyclyl or heteroaryl, optionally        substituted with one or more, in one embodiment, one, two or        three Q⁷ groups; each Q⁷ is independently selected from halo,        deuterium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl,        hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,        cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl,        heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2;

n is 1; and

q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula III orpharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof,

wherein:

R¹ and R² are each independently selected from hydrogen, halogen, alkoxyand hydroxyl;

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, aryl, heterocyclyl or heteroaryl, where R⁴ isoptionally substituted with one or more, in one embodiment, one tothree, in another embodiment, one, two or three groups selected from Q¹;

each Q¹ is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl,cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x);

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S or NH;

each W is independently CR⁸ or N;

R⁸ is hydrogen, halo, haloalkyl or alkyl;

ring A is heteroaryl or heterocyclyl optionally substituted with one tofour substituents selected from Q²;

W² is N or CR^(9b);

W³ is N or CR^(10b);

W⁴ is N or CR^(11b);

R^(9b), R^(11b) and Rub are selected as follows:

-   -   i) R^(9b), R^(10b) and R^(11b) are each independently hydrogen,        oxo, hydroxyl, halo or alkyl; or    -   ii) R^(9b) and R^(10b) or R^(10b) and R^(11b) together with the        atoms to which they are attached form an aryl or heteroaryl        ring, optionally substituted with one or more, in one        embodiment, one to three, in another embodiment, one, two or        three groups selected from Q²; and the remainder of R^(9b),        R^(10b) and R^(11b) is hydrogen, halo or alkyl; each Q² is        independently halo, cyano, oxo, thioxo, alkyl, haloalkyl,        aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,        cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl,        heteroaralkyl, heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),        —R^(u)OR^(u)OR^(x), —R^(u)OR^(u)N(R^(y))(R^(z)),        —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x), —R^(u)C(J)R^(x),        —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),        —R^(u)C(J)R^(u)N(R^(y))(R^(z)), —R^(u)C(J)N(R^(y))OR^(x),        —C(═NOR^(x))R^(x), —R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x),        —R^(u)N(R^(x))C(J)OR^(x), —R^(u)N(R^(x))S(O)_(t)R^(w) or        —C(═NR^(y))N(R^(y))OR^(x), where the alkyl, haloalkyl,        aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,        heteroaryl, and heterocyclyl groups are optionally substituted        with one or more Q⁴ groups; each Q⁴ is independently selected        from halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

each R^(u) is independently alkylene, alkenylene or a direct bond;

R^(w) is alkyl;

each R^(x) is independently hydrogen or alkyl;

R^(y) and R^(z) are each independently hydrogen or alkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2;

n is 1 or 2; and

q is an integer from 0-4;

wherein the compounds are selected such that when i) when W is CH; W¹ isC; Z is S; R¹ is hydrogen, or hydroxyl and R² is hydrogen, or R¹ and R²together form ═O; then ring A is not pyridine and ii) W is CH; W¹ is N;Z is S; R¹ and R² are hydrogen, then ring A is not pyrrolidine.

In certain embodiments, provided herein are compounds of Formula III orpharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof, wherein

R¹ and R² are each independently selected from hydrogen or halogen;

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, optionally substituted with one or more, in oneembodiment, one to three, in another embodiment, one, two or threegroups selected from Q¹;

each Q¹ is independently deuterium, halo, cyano, oxo, thioxo, alkyl,haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w), ═NOR^(d), or —C(═NR^(y))N(R^(y))OR^(x),where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q³ groups, in one embodiment, one to threeQ³ groups; each Q³ is independently selected from deuterium, halo,hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NH;

each W is independently CR⁸ or N;

R⁸ is hydrogen, halo, haloalkyl or alkyl;

ring A is heteroaryl optionally substituted with one to foursubstituents selected from Q²;

W² is N or CR^(9b);

W³ is N or CR^(10b);

W⁴ is N or CR^(11b);

R^(9b), R^(10b) and R^(11b) are selected as follows:

-   -   i) R^(9b), R^(10b) and R^(11b) are each independently hydrogen,        oxo, hydroxyl, halo or alkyl; or    -   ii) R^(9b) and R^(10b) or R^(10b) and R^(11b), together with the        atoms to which they are attached, form an aryl or heteroaryl        ring, optionally substituted with one or more, in one        embodiment, one to three, in another embodiment, one, two or        three groups selected from Q²; and the remainder of R^(9b),        R^(10b) and R^(11b) is hydrogen, halo or alkyl;

each Q² is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl,aminoalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)OR^(x), —R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)),—R^(u)SR^(x), —R^(u)C(J)R^(x), —R^(u)C(J)OR^(x),—R^(u)C(J)N(R^(y))(R^(z)), —R^(u)C(J)R^(u)N(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —C(═NOR^(x))R^(x), —R^(u)S(O)_(t)R^(w),—R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w) or —C(═NR^(y))N(R^(y))OR^(x), where thealkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q⁴ groups; each Q⁴ is independentlyselected from halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

R^(d) is hydrogen or alkyl;

each R^(u) is independently alkylene, alkenylene or a direct bond;

R^(w) is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl;

each R^(x) is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl;

R^(y) and R^(z) are each independently selected from (i) or (ii) below:

(i) R^(y) and R^(z) are each independently hydrogen, alkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl; or

(ii) R^(y) and R^(z), together with the nitrogen atom to which they areattached, form a heterocyclyl or heteroaryl, optionally substituted withone or more, in one embodiment, one, two or three Q⁷ groups; each Q⁷ isindependently selected from halo, deuterium, oxo, thioxo, hydroxy,alkoxy, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl,aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2;

n is 1 or 2; and

q is an integer from 0-2.

In certain embodiments, provided herein are compounds of Formula IIIwherein n is 1 and the other variables are as described elsewhereherein. In certain embodiments, provided herein are compounds of FormulaIII wherein each Q¹ is independently halo, oxo, alkyl, haloalkyl,hydroxyalkyl, cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x); eachR^(u) is independently alkylene or a direct bond; each R^(x) isindependently hydrogen or alkyl; n is 1 and the other variables are asdescribed elsewhere herein.

In certain embodiments, provided herein are compounds of Formula III orpharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof, wherein

R¹ and R² are each independently selected from hydrogen or halogen;

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, optionally substituted with one or more, in oneembodiment, one to three, in another embodiment, one, two or threegroups selected from Q¹;

each Q¹ is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl,cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x);

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NH;

each W is independently CR⁸ or N;

R⁸ is hydrogen, halo, haloalkyl or alkyl;

ring A is heteroaryl optionally substituted with one to foursubstituents selected from Q²;

W² is N or CR^(9b);

W³ is N or CR^(10b);

W⁴ is N or CR^(11b);

R^(9b), R^(10b) and R^(11b) are selected as follows:

-   -   i) R^(9b), R^(10b) and R^(11b) are each independently hydrogen,        oxo, hydroxyl, halo or alkyl; or    -   ii) R^(9b) and R^(10b) or R^(10b) and R^(11b), together with the        atoms to which they are attached, form an aryl or heteroaryl        ring, optionally substituted with one or more, in one        embodiment, one to three, in another embodiment, one, two or        three groups selected from Q²; and the remainder of R^(9b),        R^(10b) and R^(11b) is hydrogen, halo or alkyl;

each Q² is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl,aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x),—R^(u)N(R^(x))C(J)OR^(x), —R^(u)N(R^(x))S(O)_(t)R^(w) or—C(═NR^(y))N(R^(y))OR^(x), where the alkyl, haloalkyl, aminoalkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, andheterocyclyl groups are optionally substituted with one or more Q⁴groups; each Q⁴ is independently selected from halo, hydroxyl, alkyl,haloalkyl and hydroxyalkyl;

each R^(u) is independently alkylene or a direct bond;

R^(w) is alkyl;

each R^(x) is independently hydrogen or alkyl;

R^(y) and R^(z) are each independently hydrogen or alkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2;

n is 1 or 2; and

q is an integer from 0-2.

In certain embodiments, provided herein are compounds of Formula III orpharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof, wherein

R¹ and R² are each independently selected from hydrogen or halogen;

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, optionally substituted with one or more, in oneembodiment, one to three, in another embodiment, one, two or threegroups selected from Q¹;

each Q¹ is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl,cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x);

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NH;

each W is independently CR⁸ or N;

R⁸ is hydrogen, halo, haloalkyl or alkyl;

ring A is heteroaryl, optionally substituted with one to foursubstituents selected from Q²;

W² is N or CR^(9b);

W³ is N or CR^(10b);

W⁴ is N or CR^(11b);

R^(9b) and R^(10b), together with the atoms to which they are attached,form an aryl or heteroaryl ring, optionally substituted with one or twogroups selected from Q²;

each Q² is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl,aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x),—R^(u)N(R^(x))C(J)OR^(x), —R^(u)N(R^(x))S(O)_(t)R^(w) or—C(═NR^(y))N(R^(y))OR^(x), where the alkyl, haloalkyl, aminoalkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, andheterocyclyl groups are optionally substituted with one or more Q⁴groups; each Q⁴ is independently selected from halo, hydroxyl, alkyl,haloalkyl and hydroxyalkyl;

each R^(u) is independently alkylene or a direct bond;

R^(w) is alkyl;

each R^(x) is independently hydrogen or alkyl;

R^(y) and R^(z) are each independently hydrogen or alkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2;

R^(11b) is hydrogen;

n is 1 or 2; and

q is an integer from 0-2.

In certain embodiments, provided herein are compounds of Formula III orpharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof, wherein

R¹ and R² are each independently selected from hydrogen or halogen;

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, optionally substituted with one or more, in oneembodiment, one to three, in another embodiment, one, two or threegroups selected from Q¹;

each Q¹ is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl,cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x); Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NH;

each W is independently CR⁸ or N;

R⁸ is hydrogen, halo, haloalkyl or alkyl;

ring A is heteroaryl, optionally substituted with one to foursubstituents selected from Q²;

W² is N or CR^(9b);

W³ is N or CR^(10b);

W⁴ is N or CR^(11b);

R^(9b) and R^(10b), together with the atoms to which they are attached,form an aryl or heteroaryl ring, optionally substituted with one or twogroups selected from Q²;

each Q² is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl,aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x),—R^(u)N(R^(x))C(J)OR^(x), —R^(u)N(R^(x))S(O)_(t)R^(w) or—C(═NR^(y))N(R^(y))OR^(x), where the alkyl, haloalkyl, aminoalkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, andheterocyclyl groups are optionally substituted with one or more Q⁴groups; each Q⁴ is independently selected from halo, hydroxyl, alkyl,haloalkyl and hydroxyalkyl;

each R^(u) is independently alkylene or a direct bond;

R^(w) is alkyl;

each R^(x) is independently hydrogen or alkyl;

R^(y) and R^(z) are each independently hydrogen or alkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2;

R^(11b) is hydrogen;

n is 1 or 2; and

q is an integer from 0-2.

In certain embodiments, provided herein are compounds of Formula III orpharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof, wherein

R¹ and R² are each independently selected from hydrogen or halogen;

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, optionally substituted with one or more, in oneembodiment, one to three, in another embodiment, one, two or threegroups selected from Q¹;

each Q¹ is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl,cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x);

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NH;

each W is independently CR⁸ or N;

R⁸ is hydrogen, halo, haloalkyl or alkyl;

ring A is heteroaryl, optionally substituted with one to foursubstituents selected from Q²;

W² is N or CR^(9b);

W³ is N or CR^(10b);

W⁴ is N or CR^(11b);

R^(9b) and R^(10b), together with the carbon atoms to which they areattached, form an aryl or heteroaryl ring, optionally substituted withone or two groups Q², each Q² is independently halo, cyano, alkyl,haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl,heterocyclyl, —R^(u)OR^(x), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x),—R^(u)N(R^(x))C(J)OR^(x), —R^(u)N(R^(x))S(O)_(t)R^(w) or—C(═NR^(y))N(R^(y))OR^(x), where the cycloalkyl, heteroaryl,heterocyclyl are optionally substituted with one or more alkyl;

R^(11b) is hydrogen or Q²;

each R^(u) is independently alkylene or a direct bond;

R^(w) is alkyl;

each R^(x) is independently hydrogen or alkyl;

R^(y) and R^(z) are each independently hydrogen or alkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2; and

q is an integer from 0-2.

In certain embodiments, provided herein are compounds of Formula III orpharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof, wherein

R¹ and R² are each independently selected from hydrogen or halogen;

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, optionally substituted with one or more, in oneembodiment, one to three, in another embodiment, one, two or threegroups selected from Q¹;

each Q¹ is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl,cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x);

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NH;

each W is independently CR⁸ or N;

R⁸ is hydrogen, halo, haloalkyl or alkyl;

ring A is heteroaryl, optionally substituted with one to foursubstituents selected from Q²;

W² is N or CR^(9b);

W³ is N or CR^(10b);

W⁴ is N or CR^(11b);

R^(9b) and R^(10b), together with the carbon atoms to which they areattached, form an aryl or heteroaryl ring, optionally substituted withone or two groups Q², each Q² is independently halo, cyano, alkyl,haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl,heterocyclyl, —R^(u)OR^(x), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x),—R^(u)N(R^(x))C(J)OR^(x), —R^(u)N(R^(x))S(O)_(t)R^(w) or—C(═NR^(y))N(R^(y))OR^(x), where the cycloalkyl, heteroaryl,heterocyclyl are optionally substituted with one or more alkyl;

each R^(u) is independently alkylene or a direct bond;

R^(w) is alkyl;

each R^(x) is independently hydrogen or alkyl;

R^(y) and R^(z) are each independently hydrogen or alkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2; and

q is an integer from 0-2.

In certain embodiments, provided herein are compounds of Formula III orpharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof wherein:

R¹ and R² are each independently selected from hydrogen, halogen, andhydroxyl;

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, where R⁴ is optionally substituted with one or more,in one embodiment, one to three, in another embodiment, one, two orthree groups selected from Q¹;

each Q¹ is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl,cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x);

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NH;

each W is independently CR⁸ or N;

R⁸ is hydrogen, halo, haloalkyl or alkyl;

ring A is heteroaryl, optionally substituted with one to foursubstituents selected from Q²;

W² is N or CR^(9b);

W³ is N or CR^(10b);

W⁴ is N or CR^(11b);

R^(9b), R^(10b) and R^(11b) are selected as follows:

-   -   i) R^(9b), R^(10b) and R^(11b) are each independently hydrogen        or Q²; or    -   ii) R^(9b) and R^(10b) or R^(10b) and R^(11b), together with the        atoms on which they are substituted form an aryl, heteroaryl        ring, optionally substituted with one or two groups selected        from Q²; and the remainder of R^(9b) or R^(11b) is hydrogen or        Q²;

each Q² is hydrogen, halo, alkoxy, tetrazole or pyrazole, where thetetrazole and pyrazole rings are optionally substituted with one or morealkyl;

each R^(u) is independently alkylene or a direct bond;

R^(w) is alkyl;

each R^(x) is independently hydrogen or alkyl;

R^(y) and R^(z) are each independently hydrogen or alkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2;

n is 1 or 2; and

q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula III orpharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof

wherein:

R¹ and R² are each independently selected from hydrogen, halogen, andhydroxyl;

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, where R⁴ is optionally substituted with one or more,in one embodiment, one to three, in another embodiment, one, two orthree groups selected from Q¹;

each Q¹ is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl,cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x);

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NH;

each W is independently CR⁸ or N;

R⁸ is hydrogen, halo, haloalkyl or alkyl;

ring A is heteroaryl, optionally substituted with one to foursubstituents selected from Q²;

W² is N or CR^(9b);

W³ is N or CR^(10b);

W⁴ is N or CR^(11b);

R^(9b), R^(10b) and R^(11b) are selected as follows:

-   -   i) R^(9b), R^(10b) and R^(11b) are each independently hydrogen,        oxo, hydroxyl, halo or alkyl; or    -   ii) R^(9b) and R^(10b) or R^(10b) and R^(11b), together with the        atoms on which they are substituted form an aryl, heteroaryl        ring, optionally substituted with one or two groups selected        from Q²; and the remainder of R^(9b), R^(10b) or R^(11b) is        hydrogen or alkyl;

each Q² is hydrogen, halo, alkoxy, tetrazole or pyrazole, where thetetrazole and pyrazole rings are optionally substituted with one or morealkyl;

each R^(u) is independently alkylene or a direct bond;

R^(w) is alkyl;

each R^(x) is independently hydrogen or alkyl;

R^(y) and R^(z) are each independently hydrogen or alkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2;

n is 1 or 2; and

q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula IIIwherein W⁴ is N; W² is CR^(9b); W³ is CR^(11b); R^(9b) and R^(10b),together with the atoms to which they are attached, form an aryl orheteroaryl ring, optionally substituted with one or more, in oneembodiment, one to three, in another embodiment, one, two or threegroups selected from Q²; and the other variables are as describedelsewhere herein.

In certain embodiments, provided herein are compounds of Formula IV

or pharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof, wherein the variables are as described elsewhereherein.

In certain embodiments, provided herein are compounds of Formula IV,

wherein

R¹ and R² are each independently selected from hydrogen or halogen;

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl, whereR⁴ is optionally substituted with one or more, in one embodiment, one tothree, in another embodiment, one, two or three groups selected from Q¹;

each Q¹ is independently deuterium, halo, cyano, oxo, thioxo, alkyl,haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w), ═NOR^(d), or —C(═NR^(y))N(R^(y))OR^(x),where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q³ groups, in one embodiment, one to threeQ³ groups; each Q³ is independently selected from deuterium, halo,hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NH;

each W is independently CR⁸ or N;

R⁸ is hydrogen, halo, haloalkyl or alkyl;

W¹ is N or C;

W² is N or CR^(9b);

R^(9b) is hydrogen or Q²;

W⁴ is N or CR^(11b);

W⁵ is N or CR¹³;

R^(11b) and R¹³ are each independently hydrogen or Q²;

Q² is halo, deuterium, cyano, oxo, thioxo, alkyl, haloalkyl,haloalkenyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)OR^(x), —R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)),—R^(u)SR^(x), —R^(u)C(J)R^(x), —R^(u)C(J)OR^(x),—R^(u)C(J)N(R^(y))(R^(z)), —R^(u)C(J)R^(u)N(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —C(═NOR^(x))R^(x), —R^(u)S(O)_(t)R^(w),—R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w) or —C(═NR^(y))N(R^(y))OR^(x), where thealkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more groups Q⁴; in one embodiment, one to threeQ⁴ groups, each Q⁴ is independently selected from halo, deuterium,hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

Q⁵ and Q⁶ are each independently hydrogen, deuterium, halo, cyano, oxo,thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl,aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl,—R^(u)OR^(x), —R^(u)OR^(u)OR^(x), —R^(u)OR^(u)N(R^(y))(R^(z)),—R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x), —R^(u)C(J)R^(x), —R^(u)C(J)OR^(x),—R^(u)C(J)N(R^(y))(R^(z)), —R^(u)C(J)R^(u)N(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —C(═NOR^(x))R^(x), —R^(u)S(O)_(t)R^(w),—R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w) or —C(═NR^(y))N(R^(y))OR^(x), where thealkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q⁸ groups; each Q⁸ is independentlyselected from halo, deuterium, hydroxyl, alkyl, haloalkyl andhydroxyalkyl;

each R^(d) is independently hydrogen or alkyl;

R^(d) is hydrogen or alkyl;

each R^(u) is independently alkylene, alkenylene or a direct bond;

R^(w) is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl;

each R^(x) is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl;

R^(y) and R^(z) are each independently selected from (i) or (ii) below:

-   -   (i) R^(y) and R^(z) are each independently hydrogen, alkyl,        haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl,        cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl,        heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or        heteroaralkyl; or    -   (ii) R^(y) and R^(z), together with the nitrogen atom to which        they are attached, form a heterocyclyl or heteroaryl, optionally        substituted with one or more, in one embodiment, one, two or        three Q⁷ groups; each Q⁷ is independently selected from halo,        deuterium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl,        hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,        cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl,        heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2; and

q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula IVwherein R¹ and R² are both hydrogen. In certain embodiments, providedherein are compounds of Formula IV wherein R^(9b) and R^(11b) are eachindependently hydrogen, alkyl or haloalkyl and the other variables areas described elsewhere herein. In certain embodiments, provided hereinare compounds Formula IV wherein each Q¹ is independently halo, oxo,alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, ═NOH, —R^(u)OR^(x) or—R^(u)C(O)R^(x); each R^(u) is independently alkylene or a direct bond;each R^(x) is independently hydrogen or alkyl; and the other variablesare as described elsewhere herein. In certain embodiments, providedherein are compounds Formula IV wherein each Q¹ is independently halo,oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, ═NOH, —R^(u)OR^(x) or—R^(u)C(O)R^(x); each R^(u) is independently alkylene or a direct bond;each R^(x) is independently hydrogen or alkyl; R^(11b) and R¹³ are eachindependently hydrogen, halo or alkyl and the other variables are asdescribed elsewhere herein. In certain embodiments, provided herein arecompounds of Formula IV wherein R⁴ is cycloalkyl.

In certain embodiments, provided herein are compounds of Formula IVwherein R^(9b) and R^(11b) are each independently hydrogen, halo oralkyl and the other variables are as described elsewhere herein. Incertain embodiments, provided herein are compounds Formula IV whereineach Q¹ is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl,cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x); each R^(u) isindependently alkylene or a direct bond; each R^(x) is independentlyhydrogen or alkyl; and the other variables are as described elsewhereherein. In certain embodiments, provided herein are compounds Formula IVwherein each Q¹ is independently halo, oxo, alkyl, haloalkyl,hydroxyalkyl, cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x); eachR^(u) is independently alkylene or a direct bond; each R^(x) isindependently hydrogen or alkyl; R^(11b) and R¹³ are each independentlyhydrogen, halo or alkyl and the other variables are as describedelsewhere herein.

In certain embodiments, provided herein are compounds of Formula IV orpharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof, wherein:

R¹ and R² are each independently selected from hydrogen or halogen;

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl, whereR⁴ is optionally substituted with one or more, in one embodiment, one tothree, in another embodiment, one, two or three groups selected from Q¹;

each Q¹ is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl,cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x);

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NH;

each W is independently CR⁸ or N;

R⁸ is hydrogen, halo, haloalkyl or alkyl;

W¹ is N or C;

W² is N or CR^(9b);

R^(9b) is hydrogen or alkyl;

W⁴ is N or CR^(11b);

R^(11b) is hydrogen, halo or alkyl;

W⁵ is N or CR¹³;

R¹³ is hydrogen, halo or alkyl;

Q⁵ and Q⁶ are each independently hydrogen, deuterium, halo, cyano, oxo,thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl,—R^(u)OR^(x), —R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)),—R^(u)SR^(x), —R^(u)C(J)R^(x), —R^(u)C(J)OR^(x),—R^(u)C(J)N(R^(y))(R^(z)), —R^(u)C(J)N(R^(y))OR^(x),—R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w) or —C(═NR^(y))N(R^(y))OR^(x), where thealkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q⁸ groups; each Q⁸ is independentlyselected from halo, deuterium, hydroxyl, alkyl, haloalkyl andhydroxyalkyl;

each R^(u) is independently alkylene or a direct bond;

R^(w) is alkyl;

each R^(x) is independently hydrogen or alkyl;

R^(y) and R^(z) are each independently hydrogen or alkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2; and

q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula IV orpharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof,

wherein:

R¹ and R² are each independently selected from hydrogen or halogen;

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl, whereR⁴ is optionally substituted with one or more, in one embodiment, one tothree, in another embodiment, one, two or three groups selected from Q¹;

each Q¹ is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl,cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x); Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NH;

each W is independently CR⁸ or N;

R⁸ is hydrogen, halo, haloalkyl or alkyl;

W¹ is N or C;

W² is N or CR^(9b);

R^(9b) is hydrogen or alkyl;

W⁴ is N or CR^(11b);

R^(11b) is hydrogen or Q²;

Q² is halo, deuterium, cyano, oxo, thioxo, alkyl, haloalkyl,haloalkenyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)OR^(x), —R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)),—R^(u)SR^(x), —R^(u)C(J)R^(x), —R^(u)C(J)OR^(x),—R^(u)C(J)N(R^(y))(R^(z)), —R^(u)C(J)R^(u)N(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —C(═NOR^(x))R^(x), —R^(u)S(O)_(t)R^(w),—R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w) or —C(═NR^(y))N(R^(y))OR^(x), where thealkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more groups Q⁴; in one embodiment, one to threeQ⁴ groups, each Q⁴ is independently selected from halo, deuterium,hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

W⁵ is N or CR¹³;

R¹³ is hydrogen, halo or alkyl;

Q⁵ and Q⁶ are each independently hydrogen, deuterium, halo, cyano, oxo,thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl,aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl,—R^(u)OR^(x), —R^(u)OR^(u)OR^(x), —R^(u)OR^(u)N(R^(y))(R^(z)),—R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x), —R^(u)C(J)R^(x), —R^(u)C(J)OR^(x),—R^(u)C(J)N(R^(y))(R^(z)), —R^(u)C(J)R^(u)N(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —C(═NOR^(x))R^(x), —R^(u)S(O)_(t)R^(w),—R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w) or —C(═NR^(y))N(R^(y))OR^(x), where thealkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q⁸ groups; each Q⁸ is independentlyselected from halo, deuterium, hydroxyl, alkyl, haloalkyl andhydroxyalkyl;

each R^(u) is independently alkylene, alkenylene or a direct bond;

R^(w) is alkyl;

each R^(x) is independently hydrogen or alkyl;

R^(y) and R^(z) are each independently hydrogen or alkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2; and

q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula IV orpharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof,

wherein:

R¹ and R² are each independently selected from hydrogen or halogen;

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl, whereR⁴ is optionally substituted with one or more, in one embodiment, one tothree, in another embodiment, one, two or three groups selected from Q¹;

each Q¹ is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl,cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x);

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NH;

each W is independently CR⁸ or N;

R⁸ is hydrogen, halo, haloalkyl or alkyl;

W¹ is N or C;

W² is N or CR^(9b);

R^(9b) is hydrogen or alkyl;

W⁴ is N or CR^(11b);

R^(11b) is hydrogen, halo or alkyl;

W⁵ is N or CR¹³;

R¹³ is hydrogen, halo or alkyl;

Q⁵ and Q⁶ are each independently hydrogen, deuterium, halo, cyano, oxo,thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl,

heterocyclylalkyl, —R^(u)OR^(x), —R^(u)OR^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)), —R^(u)C(J)R^(u)N(R^(y))(R^(z)), —R^(u)C(J)N(R^(y))OR^(x), —C(═NOR^(x))R^(x),—R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w) or —C(═NR^(y))N(R^(y))OR^(x), where thealkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q⁸ groups; each Q⁸ is independentlyselected from halo, deuterium, hydroxyl, alkyl, haloalkyl andhydroxyalkyl;

each R^(u) is independently alkylene, alkenylene or a direct bond;

R^(w) is alkyl;

each R^(x) is independently hydrogen or alkyl;

R^(y) and R^(z) are each independently hydrogen or alkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2; and

q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula IVwherein R¹ and R² are both hydrogen and the other variables are asdescribed elsewhere herein.

In certain embodiments, provided herein are compounds of Formula IVwherein R^(11b) and R¹³ are each independently hydrogen, halo or alkyland the other variables are as described elsewhere herein.

In certain embodiments, provided herein are compounds of Formula V

or pharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof, wherein the variables are as described elsewhereherein.

In certain embodiments, provided herein are compounds of Formula V orpharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof,

wherein

R¹ and R² are each independently selected from hydrogen or halogen;

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, aryl, heterocyclyl or heteroaryl, where R⁴ isoptionally substituted with one or more, in one embodiment, one tothree, in another embodiment, one, two or three groups selected from Q¹;

each Q¹ is independently deuterium, halo, cyano, oxo, thioxo, alkyl,haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w), ═NOR^(d), or —C(═NR^(y))N(R^(y))OR^(x),where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q³ groups, in one embodiment, one to threeQ³ groups; each Q³ is independently selected from deuterium, halo,hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NH;

each W is independently CR⁸ or N;

R⁸ is hydrogen, halo, haloalkyl or alkyl;

W⁴ is N or CR^(11b);

W⁵ is N or CR¹³;

R^(11b) and R¹³ are each independently hydrogen or Q²;

Q² is halo, deuterium, cyano, oxo, thioxo, alkyl, haloalkyl,haloalkenyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)OR^(x), —R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)),—R^(u)SR^(x), —R^(u)C(J)R^(x), —R^(u)C(J)OR^(x),—R^(u)C(J)N(R^(y))(R^(z)), —R^(u)C(J)RN(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —C(═NOR^(x))R^(x), —R^(u)S(O)_(t)R^(w),—R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w) or —C(═NR^(y))N(R^(y))OR^(x), where thealkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more groups Q⁴; in one embodiment, one to threeQ⁴ groups, each Q⁴ is independently selected from halo, deuterium,hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

Q⁵ and Q⁶ are each independently hydrogen, deuterium, halo, cyano, oxo,thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl,aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl,—R^(u)OR^(x), —R^(u)OR^(u)OR^(x), —R^(u)OR^(u)N(R^(y))(R^(z)),—R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x), —R^(u)C(J)R^(x), —R^(u)C(J)OR^(x),—R^(u)C(J)N(R^(y))(R^(z)), —R^(u)C(J)RN(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —C(═NOR^(x))R^(x), —R^(u)S(O)_(t)R^(w),—R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w) or —C(═NR^(y))N(R^(y))OR^(x), where thealkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q⁸ groups; each Q⁸ is independentlyselected from halo, deuterium, hydroxyl, alkyl, haloalkyl andhydroxyalkyl;

each R^(d) is independently hydrogen or alkyl;

each R^(u) is independently alkylene, alkenylene or a direct bond;

R^(w) is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl;

each R^(x) is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl;

R^(y) and R^(z) are each independently selected from (i) or (ii) below:

-   -   (i) R^(y) and R^(z) are each independently hydrogen, alkyl,        haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl,        cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl,        heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or        heteroaralkyl; or    -   (ii) R^(y) and R^(z), together with the nitrogen atom to which        they are attached, form a heterocyclyl or heteroaryl, optionally        substituted with one or more, in one embodiment, one, two or        three Q⁷ groups; each Q⁷ is independently selected from halo,        deuterium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl,        hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,        cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl,        heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl;

R^(y) and R^(z) are each independently hydrogen or alkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2; and

q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula V orpharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof,

wherein:

R¹ and R² are each independently selected from hydrogen or halogen;

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, aryl, heterocyclyl or heteroaryl, where R⁴ isoptionally substituted with one or more, in one embodiment, one tothree, in another embodiment, one, two or three groups selected from Q¹;

each Q¹ is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl,cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x);

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NH;

each W is independently CR⁸ or N;

R⁸ is hydrogen, halo, haloalkyl or alkyl;

W⁴ is N or CR^(11b);

R^(11b) is hydrogen, halo or alkyl;

W⁵ is N or CR¹³;

R¹³ is hydrogen, halo or alkyl;

Q⁵ and Q⁶ are each independently hydrogen, deuterium, halo, cyano, oxo,thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl,—R^(u)OR^(x), —R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)),—R^(u)SR^(x), —R^(u)C(J)R^(x), —R^(u)C(J)OR^(x),—R^(u)C(J)N(R^(y))(R^(z)), —R^(u)C(J)N(R^(y))OR^(x),—R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w) or —C(═NR^(y))N(R^(y))OR^(x), where thealkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q⁸ groups; each Q⁸ is independentlyselected from halo, deuterium, hydroxyl, alkyl, haloalkyl andhydroxyalkyl;

each R^(u) is independently alkylene or a direct bond;

R^(w) is alkyl;

each R^(x) is independently hydrogen or alkyl;

R^(y) and R^(z) are each independently hydrogen or alkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2; and

q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula Vwherein W⁴ is N and the other variables are as described elsewhereherein.

In certain embodiments, provided herein are compounds of Formula Vwherein W⁴ is N; W⁵ is N; Q⁵ and Q⁶ are each independently hydrogen,halo, or alkoxy; R⁴ is cycloalkyl, optionally substituted with one ortwo groups selected from Q¹; each Q¹ is independently halo, oxo, alkyl,haloalkyl, hydroxyalkyl, cycloalkyl, ═NOH, —R^(u)OR^(x) or—R^(u)C(O)R^(x); and the other variables are as described elsewhereherein.

In certain embodiments, provided herein are compounds of Formula Vwherein W⁴ is N; W⁵ is CR^(11b); R^(11b) is hydrogen; Q⁵ and Q⁶ are eachindependently hydrogen, halo, or alkoxy; R⁴ is cycloalkyl, optionallysubstituted with one or two groups selected from Q¹; each Q¹ isindependently halo, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl,═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x); and the other variables are asdescribed elsewhere herein.

In certain embodiments, provided herein are compound of Formula Vwherein Q¹ is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl,cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x); each R^(u) isindependently alkylene or a direct bond; each R^(x) is independentlyhydrogen or alkyl; and the other variables are as described elsewhereherein.

In certain embodiments, provided herein are compounds of Formula Vwherein W⁴ is N; W⁵ is CH or N; Q⁵ and Q⁶ are each independentlyhydrogen, halo, or alkoxy; R⁴ is cyclohexyl, optionally substituted withone or two hydroxy; and the other variables are as described elsewhereherein.

In certain embodiments, provided herein are compounds of Formula Vwherein W is C; Z is S; W⁴ is N; W⁵ is CH or N; Q⁵ and Q⁶ are eachindependently hydrogen, halo, alkyl, or alkoxy; R³ is hydrogen or alkyl;Y is —(CR⁵R⁶)_(q)—; q is 0; and R⁴ is cycloalkyl, optionally substitutedwith one or two hydroxy.

In certain embodiments, provided herein are compounds of Formula Vwherein W is C; Z is S; W⁴ is N; W⁵ is CH or N; Q⁵ and Q⁶ are eachindependently hydrogen, halo, alkyl, or alkoxy; R³ is hydrogen or alkyl;Y is —(CR⁵R⁶)_(q)—; q is 0; and R⁴ is cyclohexyl, optionally substitutedwith one or two hydroxy.

In certain embodiments, provided herein are compounds of Formula V orpharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof,

wherein:

R¹ and R² are each independently selected from hydrogen or halogen;

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, aryl, heterocyclyl or heteroaryl, where R⁴ isoptionally substituted with one or more, in one embodiment, one tothree, in another embodiment, one, two or three groups selected from Q¹;

each Q¹ is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl,cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x);

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NH;

each W is independently CR⁸ or N;

R⁸ is hydrogen, halo, haloalkyl or alkyl;

W⁴ is N or CR^(11b);

R^(11b) is hydrogen, halo or alkyl;

W⁵ is N or CR¹³;

R¹³ is hydrogen, halo or alkyl;

Q⁵ and Q⁶ are each independently hydrogen, deuterium, halo, cyano, oxo,thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl,—R^(u)OR^(x), —R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)OR^(u)OR^(x),—R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x), —R^(u)C(J)R^(x), —R^(u)C(J)OR^(x),—R^(u)C(J)N(R^(y))(R^(z)), —R^(u)C(J)R^(u)N(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —C(═NOR^(x)) R^(x), —R^(u)S(O)_(t)R^(w),—R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w) or —C(═NR^(y))N(R^(y))OR^(x), where thealkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q⁸ groups; each Q⁸ is independentlyselected from halo, deuterium, hydroxyl, alkyl, haloalkyl andhydroxyalkyl;

each R^(u) is independently alkylene, alkenylene or a direct bond;

R^(w) is alkyl;

each R^(x) is independently hydrogen or alkyl;

R^(y) and R^(z) are each independently hydrogen or alkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2; and

q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula VI

or pharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof

wherein

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, aryl, heterocyclyl or heteroaryl, where R⁴ isoptionally substituted with one or more, in one embodiment, one tothree, in another embodiment, one, two or three groups selected from Q¹;

each Q¹ is independently deuterium, halo, cyano, oxo, thioxo, alkyl,haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w), ═NOR^(d), or —C(═NR^(y))N(R^(y))OR^(x),where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q³ groups, in one embodiment, one to threeQ³ groups; each Q³ is independently selected from deuterium, halo,hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NH;

W⁵ is N or CH;

W⁴ is N or CR^(11b);

R^(11b) is hydrogen or Q²;

Q² is halo, deuterium, cyano, oxo, thioxo, alkyl, haloalkyl,haloalkenyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)OR^(x), —R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)),—R^(u)SR^(x), —R^(u)C(J)R^(x), —R^(u)C(J)OR^(x),—R^(u)C(J)N(R^(y))(R^(z)), —R^(u)C(J)R^(u)N(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —C(═NOR^(x))R^(x), —R^(u)S(O)_(t)R^(w),—R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w) or —C(═NR^(y))N(R^(y))OR^(x), where thealkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more groups Q⁴; in one embodiment, one to threeQ⁴ groups, each Q⁴ is independently selected from halo, deuterium,hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

Q⁵ and Q⁶ are each independently hydrogen, deuterium, halo, cyano, oxo,thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl,aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl,—R^(u)OR^(x), —R^(u)OR^(u)OR^(x), —R^(u)OR^(u)N(R^(y))(R^(z)),—R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x), —R^(u)C(J)R^(x), —R^(u)C(J)OR^(x),—R^(u)C(J)N(R^(y))(R^(z)), —R^(u)C(J)RN(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —C(═NOR^(x))R^(x), —R^(u)S(O)_(t)R^(w),—R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w) or —C(═NR^(y))N(R^(y))OR^(x), where thealkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q⁸ groups; each Q⁸ is independentlyselected from halo, deuterium, hydroxyl, alkyl, haloalkyl andhydroxyalkyl;

each R^(d) is independently hydrogen or alkyl;

each R^(u) is independently alkylene, alkenylene or a direct bond;

R^(w) is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl;

each R^(x) is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl;

R^(y) and R^(z) are each independently selected from (i) or (ii) below:

-   -   (i) R^(y) and R^(z) are each independently hydrogen, alkyl,        haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl,        cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl,        heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or        heteroaralkyl; or    -   (ii) R^(y) and R^(z), together with the nitrogen atom to which        they are attached, form a heterocyclyl or heteroaryl, optionally        substituted with one or more, in one embodiment, one, two or        three Q⁷ groups; each Q⁷ is independently selected from halo,        deuterium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl,        hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,        cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl,        heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; J        is O, NR^(x) or S;

each t is independently an integer from 0-2; and

q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula VIwherein W⁴ is N and the other variables are as described elsewhereherein. In certain embodiments, provided herein are compound of FormulaVI wherein Q¹ is independently halo, oxo, alkyl, haloalkyl,hydroxyalkyl, cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x); eachR^(u) is independently alkylene or a direct bond; each R^(x) isindependently hydrogen or alkyl; and the other variables are asdescribed elsewhere herein.

In certain embodiments, provided herein are compounds of Formula VI orpharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof wherein

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, aryl, heterocyclyl or heteroaryl, where R⁴ isoptionally substituted with one or more, in one embodiment, one tothree, in another embodiment, one, two or three groups selected from Q¹;

each Q¹ is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl,cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x);

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NH;

W⁵ is N or CH;

W⁴ is N or CR^(11b);

R^(11b) is hydrogen, halo or alkyl;

Q⁵ and Q⁶ are each independently hydrogen, deuterium, halo, cyano, oxo,thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl,—R^(u)OR^(x), —R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)),—R^(u)SR^(x), —R^(u)C(J)R^(x), —R^(u)C(J)OR^(x),—R^(u)C(J)N(R^(y))(R^(z)), —R^(u)C(J)N(R^(y))OR^(x),—R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w) or —C(═NR^(y))N(R^(y))OR^(x), where thealkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q⁸ groups; each Q⁸ is independentlyselected from halo, deuterium, hydroxyl, alkyl, haloalkyl andhydroxyalkyl;

each R^(u) is independently alkylene or a direct bond;

R^(w) is alkyl;

each R^(x) is independently hydrogen or alkyl;

R^(y) and R^(z) are each independently hydrogen or alkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2; and

q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula VI orpharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof

wherein

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, aryl, heterocyclyl or heteroaryl, where R⁴ isoptionally substituted with one or more, in one embodiment, one tothree, in another embodiment, one, two or three groups selected from Q¹;

each Q¹ is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl,cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x);

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NH;

W⁵ is N or CH;

W⁴ is N or CR^(11b);

R^(11b) is hydrogen, halo or alkyl;

Q⁵ and Q⁶ are each independently hydrogen, deuterium, halo, cyano, oxo,thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl,—R^(u)OR^(x), —R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)OR^(u)OR^(x),—R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x), —R^(u)C(J)R^(x), —R^(u)C(J)OR^(x),—R^(u)C(J)N(R^(y))(R^(z)), —R^(u)C(J)R^(u)N(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x),—R^(u)N(R^(x))C(J)OR^(x), —C(═NOR^(x))R^(x), —R^(u)N(R^(x))S(O)_(t)R^(w)or —C(═NR^(y))N(R^(y))OR^(x), where the alkyl, haloalkyl, aminoalkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, andheterocyclyl groups are optionally substituted with one or more Q⁸groups; each Q⁸ is independently selected from halo, deuterium,hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

each R^(u) is independently alkylene, alkenylene or a direct bond;

R^(w) is alkyl;

each R^(x) is independently hydrogen or alkyl;

R^(y) and R^(z) are each independently hydrogen or alkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2;

q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula VI orpharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof

wherein

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, aryl, heterocyclyl or heteroaryl, where R⁴ isoptionally substituted with one or more, in one embodiment, one tothree, in another embodiment, one, two or three groups selected from Q¹;

each Q¹ is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl,cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x);

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NH;

W⁵ is N or CH;

W⁴ is N or CR^(11b);

R^(11b) is hydrogen, halo or alkyl;

Q⁵ and Q⁶ are each independently hydrogen, deuterium, halo, cyano, oxo,thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl,—R^(u)OR^(x), —R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)),—R^(u)SR^(x), —R^(u)C(J)R^(x), —R^(u)C(J)OR^(x),—R^(u)C(J)N(R^(y))(R^(z)), —R^(u)C(J)N(R^(y))OR^(x),—R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w) or —C(═NR^(y))N(R^(y))OR^(x), where thealkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q⁸ groups; each Q⁸ is independentlyselected from halo, deuterium, hydroxyl, alkyl, haloalkyl andhydroxyalkyl;

each R^(u) is independently alkylene or a direct bond;

R^(w) is alkyl;

each R^(x) is independently hydrogen or alkyl;

R^(y) and R^(z) are each independently hydrogen or alkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2; and

q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula VI orpharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof

wherein

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, aryl, heterocyclyl or heteroaryl, where R⁴ isoptionally substituted with one or more, in one embodiment, one tothree, in another embodiment, one, two or three groups selected from Q¹;

each Q¹ is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl,cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x);

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NH;

W⁵ is N or CH;

W⁴ is N or CR^(11b);

R^(11b) is hydrogen, halo or alkyl;

Q⁵ and Q⁶ are each independently hydrogen, deuterium, halo, cyano, oxo,thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl,—R^(u)OR^(x), —R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)OR^(u)OR^(x),—R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x), —R^(u)C(J)R^(x), —R^(u)C(J)OR^(x),—R^(u)C(J)N(R^(y))(R^(z)), —R^(u)C(J)R^(u)N(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x),—R^(u)N(R^(x))C(J)OR^(x), —C(═NOR^(x))R^(x), —R^(u)N(R^(x))S(O)_(t)R^(w)or —C(═NR^(y))N(R^(y))OR^(x), where the alkyl, haloalkyl, aminoalkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, andheterocyclyl groups are optionally substituted with one or more Q⁸groups; each Q⁸ is independently selected from halo, deuterium,hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

each R^(u) is independently alkylene, alkenylene or a direct bond;

R^(w) is alkyl;

each R^(x) is independently hydrogen or alkyl;

R^(y) and R^(z) are each independently hydrogen or alkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2;

q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formulae IV, Vor VI wherein W⁴ is N, W⁵ is N or CR¹³; R¹³ is hydrogen, halo or alkyl;and the other variables are as described elsewhere herein. In certainembodiments, provided herein are compounds of Fomulae IV, V or VIwherein W⁴ is N; W⁵ is N or CH and the other variables are as describedelsewhere herein.

In certain embodiments, provided herein are compounds of Formulae IV, Vor VI, wherein Q⁵ and Q⁶ are each independently hydrogen, deuterium,halo, cyano, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl,—R^(u)OR^(x), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x), —R^(u)C(J)R^(x),—R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)), —R^(u)C(J)N(R^(y))OR^(x),—R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w) or —C(═NR^(y))N(R^(y))OR^(x), where thealkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q⁸ groups; each Q⁸ is independentlyselected from halo, deuterium, hydroxyl, alkyl, haloalkyl andhydroxyalkyl;

each R^(u) is independently alkylene or a direct bond;

R^(w) is alkyl;

each R^(x) is independently hydrogen or alkyl;

R^(y) and R^(z) are each independently hydrogen or alkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2;

n is 1 or 2; and

q is an integer from 0-4, and the other variables are as describedelsewhere herein.

In certain embodiments, Q⁵ and Q⁶ are each independently hydrogen,deuterium, chloro, fluoro, bromo, cyano, alkyl, alkenyl, alkynyl,cycloalkyl, methoxy or alkylcarbonyl, and the other variables are asdescribed elsewhere herein. In certain embodiments, provided herein arecompounds of Formula IV, V or VI, wherein Q⁵ and Q⁶ are eachindependently hydrogen, deuterium, halo, cyano, cycloalkyl, alkoxy,tetrazole or pyrazole, where the tetrazole and pyrazole rings areoptionally substituted with one or more alkyl, and the other variablesare as described elsewhere herein. In certain embodiments, providedherein are compounds of Formula IV, V or VI, wherein Q⁵ and Q⁶ are eachindependently hydrogen, deuterium, halo, alkoxy, tetrazole or pyrazole,where the tetrazole and pyrazole rings are optionally substituted withone or more alkyl, and the other variables are as described elsewhereherein. In certain embodiments, Q⁵ and Q⁶ are each independentlyhydrogen, deuterium, chloro, fluoro, bromo, cyano, alkyl, alkenyl,alkynyl, cycloalkyl, methoxy or alkylcarbonyl, and the other variablesare as described elsewhere herein. In certain embodiments, Q⁵ and Q⁶ areeach independently hydrogen, deuterium, chloro, fluoro, bromo, cyano,alkyl, alkenyl, alkynyl, cycloalkyl or methoxy, and the other variablesare as described elsewhere herein. In certain embodiments, Q⁵ and Q⁶ areeach independently hydrogen, deuterium, chloro, fluoro, bromo, cyano,cycloalkyl or methoxy, and the other variables are as describedelsewhere herein. In certain embodiments, Q⁵ and Q⁶ are eachindependently hydrogen, deuterium, chloro, fluoro, bromo or methoxy, andthe other variables are as described elsewhere herein.

In certain embodiments, provided herein are compounds of Formula IV, Vor VI, wherein

R³ is hydrogen;

R⁴ is cyclohexyl, tetrahydrofuryl, pyridinyl, phenyl, morpholinyl,cyclopentyl, piperidinyl, tetrahydro-2H-pyranyl or2,3-dihydro-1H-indenyl, where R⁴ is optionally substituted with one ormore, in one embodiment, one to three, in another embodiment, one, twoor three groups selected from Q¹; each Q¹ is independently halo, oxo,alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, ═NOH, —R^(u)OR^(x) or—R^(u)C(O)R^(x); each R^(u) is independently alkylene or a direct bond;

each R^(x) is independently hydrogen or alkyl;

Q⁵ and Q⁶ are each independently hydrogen, deuterium, halo, cyano,alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x), —R^(u)C(J)R^(x), —R^(u)C(J)OR^(x),—R^(u)C(J)N(R^(y))(R^(z)), —R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x),—R^(u)N(R^(x))C(J)OR^(x), —R^(u)N(R^(x))S(O)_(t)R^(w) or—C(═NR^(y))N(R^(y))OR^(x), where the alkyl, haloalkyl, aminoalkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, andheterocyclyl groups are optionally substituted with one or more Q⁸groups; each Q⁸ is independently selected from halo, deuterium,hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

each R^(u) is independently alkylene or a direct bond;

R^(w) is alkyl;

each R^(x) is independently hydrogen or alkyl;

R^(y) and R^(z) are each independently hydrogen or alkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2;

n is 1 or 2; and

q is an integer from 0-4, and the other variables are as describedelsewhere herein.

In certain embodiments, provided herein are compounds of Formula VIIa

or pharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof,wherein:

R¹ and R² are each independently selected from hydrogen or halogen;

R³ is hydrogen or alkyl;

each Q¹ is independently deuterium, halo, cyano, oxo, thioxo, alkyl,haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w), ═NOR^(d), or —C(═NR^(y))N(R^(y))OR^(x),where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q³ groups, in one embodiment, one to threeQ³ groups; each Q³ is independently selected from deuterium, halo,hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NH;

each W is independently CR⁸ or N;

R⁸ is hydrogen, halo, haloalkyl or alkyl;

ring A is aryl or heteroaryl, optionally substituted with one to foursubstituents selected from Q²;

W¹ is N or C;

W² is N, NR^(9a) or CR^(9b);

W³ is N, NR^(10a) or CR^(10b);

W⁴ is N, NR^(11a) or CR^(11b);

R^(9a), R^(9b), R^(10a), R^(10b), R^(11a) and R^(11b) are selected asfollows:

-   -   i) R^(9a), R^(10a) and R^(11a) are each independently hydrogen        or alkyl and R^(9b), R^(10b) and R^(11b) are each independently        hydrogen or Q²; or    -   ii) R^(9a) and R^(10b), R^(9b) and R^(10b), R^(9b) and R^(10a),        R^(10b) and R^(11a), R^(10a) and R^(11b) or R^(10b) and R^(11b),        together with the atoms to which they are attached form an aryl,        heteroaryl or heterocyclyl ring, wherein the aryl, heteroaryl or        heterocyclyl ring is optionally substituted with one or more, in        one embodiment, one to three, in another embodiment, one, two or        three groups selected from Q²; and the remainder of R^(9a) or        R^(11a) is hydrogen or alkyl and the remainder of R^(9b) or        R^(11b) is hydrogen or Q²;

each Q² is independently halo, deuterium, cyano, oxo, thioxo, alkyl,haloalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl,—R^(u)OR^(x), —R^(u)OR^(u)OR^(x), —R^(u)OR^(u)N(R^(y))(R^(z)),—R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x), —R^(u)C(J)R^(x), —R^(u)C(J)OR^(x),—^(u)C(J)N(R^(y))(R^(z)), —R^(u)C(J)R^(u)N(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —C(═NOR^(x))R^(x), —R^(u)S(O)_(t)R^(w),—R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w) or —C(═NR^(y))N(R^(y))OR^(x), where thealkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q⁴ groups; each Q⁴ is independentlyselected from halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

each R^(d) is independently hydrogen or alkyl;

each R^(u) is independently alkylene or a direct bond;

R^(w) is alkyl;

each R^(x) is independently hydrogen or alkyl;

R^(y) and R^(z) are each independently hydrogen or alkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2;

n is 1 or 2; and

q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula VIIawherein each Q¹ is independently halo, oxo, alkyl, haloalkyl,hydroxyalkyl, cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x); eachR^(u) is independently alkylene or a direct bond; each R^(x) isindependently hydrogen or alkyl; and the other variables are asdescribed elsewhere herein.

In certain embodiments, provided herein are compounds of Formula VIIa orpharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof,

wherein:

R¹ and R² are each independently selected from hydrogen or halogen;

R³ is hydrogen or alkyl;

each Q¹ is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl,cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x);

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NH;

each W is independently CR⁸ or N;

R⁸ is hydrogen, halo, haloalkyl or alkyl;

ring A is aryl or heteroaryl, optionally substituted with one to foursubstituents selected from Q²;

W¹ is N or C;

W² is N, NR^(9a) or CR^(9b);

W³ is N, NR^(10a) or CR^(10b);

W⁴ is N, NR^(11a) or CR^(11b);

R^(9a), R^(9b), R^(10a), R^(10b), R^(11a) and R^(11b) are selected asfollows:

-   -   i) R^(9a), R^(10a) and R^(11a) are each independently hydrogen        or alkyl and R^(9b), R^(10b) and R^(11b) are each independently        hydrogen, oxo, hydroxyl, halo or alkyl; or    -   ii) R^(9a) and R^(10b), R^(9b) and R^(10b), R^(9b) and R^(10a),        R^(10b) and R^(11a), R^(10a) and R^(11b) or R^(10b) and R^(11b),        together with the atoms to which they are attached form an aryl,        heteroaryl or heterocyclyl ring, wherein the aryl, heteroaryl or        heterocyclyl ring is optionally substituted with one or more, in        one embodiment, one to three, in another embodiment, one, two or        three groups selected from Q²; and the remainder of R^(9a),        R^(10a) or R^(11a) is hydrogen or alkyl and the remainder of        R^(9b), R^(10b) or R^(11b) is hydrogen, halo or alkyl;

each Q² is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl,aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x),—R^(u)N(R^(x))C(J)OR^(x), —R^(u)N(R^(x))S(O)_(t)R^(w) or—C(═NR^(y))N(R^(y))OR^(x), where the alkyl, haloalkyl, aminoalkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, andheterocyclyl groups are optionally substituted with one or more Q⁴groups; each Q⁴ is independently selected from halo, hydroxyl, alkyl,haloalkyl and hydroxyalkyl;

each R^(u) is independently alkylene or a direct bond;

R^(w) is alkyl;

each R^(x) is independently hydrogen or alkyl;

R^(y) and R^(z) are each independently hydrogen or alkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2;

n is 1 or 2; and

q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula VIIa orpharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof,

wherein:

R¹ and R² are each independently selected from hydrogen or halogen;

R³ is hydrogen or alkyl;

each Q¹ is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl,cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x);

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NH;

each W is independently CR⁸ or N;

R⁸ is hydrogen, halo, haloalkyl or alkyl;

ring A is aryl, heteroaryl or heterocyclyl, optionally substituted withone to four substituents selected from Q²;

W¹ is N or C;

W² is N, NR^(9a) or CR^(9b);

W³ is N, NR^(10a) or CR^(10b);

W⁴ is N, NR^(11a) or CR^(11b);

R^(9a), R^(9b), R^(10a), R^(10b), R^(11a) and R^(11b) are selected asfollows:

-   -   i) R^(9a), R^(10a) and R^(11a) are each independently hydrogen        or alkyl and R^(9b), R^(10b) and R^(11b) are each independently        hydrogen, oxo, hydroxyl, halo or alkyl; or    -   ii) R^(9a) and R^(10b), R^(9b) and R^(10b), R^(9b) and R^(10a),        R^(10b) and R^(11a), R^(10a) and R^(11b) or R^(10b) and R^(11b),        together with the atoms to which they are attached form an aryl,        heteroaryl or heterocyclyl ring, wherein the aryl, heteroaryl or        heterocyclyl ring is optionally substituted with one or more, in        one embodiment, one to three, in another embodiment, one, two or        three groups selected from Q²; and the remainder of R^(9a),        R^(10a) or R^(11a) is hydrogen or alkyl and the remainder of        R^(9b), R^(10b) or R^(11b) is hydrogen, halo or alkyl; or    -   iii) R^(9a) and R^(10b), R^(9b) and R^(10b), R^(9b) and R^(10a),        R^(10b) and R^(11a), R^(10a) and R^(11b) or R^(10b) and R^(11b)        together with the atoms to which they are attached form an aryl,        heteroaryl or heterocyclyl ring optionally fused to a phenyl        ring optionally substituted with one or more, in one embodiment,        one to three, in another embodiment, one, two or three groups        selected from Q²; and the remainder of R^(9a) and R^(9b) or the        remainder of R^(11a) and R^(11b) are each independently hydrogen        or alkyl;

each Q² is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl,aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x), —R^(u)OR^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)C(J)R^(u)N(R^(y))(R^(z)), —R^(u)C(J)N(R^(y))OR^(x),—C(═NOR^(x))R^(x), —R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x),—R^(u)N(R^(x))C(J)OR^(x), —R^(u)N(R^(x))S(O)_(t)R^(w) or—C(═NR^(y))N(R^(y))OR^(x), where the alkyl, haloalkyl, aminoalkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, andheterocyclyl groups are optionally substituted with one or more Q⁴groups; each Q⁴ is independently selected from halo, hydroxyl, alkyl,haloalkyl and hydroxyalkyl;

each R^(u) is independently alkylene, alkenylene or a direct bond;

R^(w) is alkyl;

each R^(x) is independently hydrogen or alkyl;

R^(y) and R^(z) are each independently hydrogen or alkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2;

n is 1 or 2; and

q is an integer from 0-4;

wherein the compounds are selected such that: i) when W is CH; W¹ is C;Z is S; R¹ is hydrogen, or hydroxyl and R² is hydrogen, or R¹ and R²together form ═O; then ring A is not pyridine and ii) when W is CH; W¹is N; Z is S; R¹ and R² are hydrogen, then ring A is not pyrrolidine.

In certain embodiments, provided herein are compounds of Formula VIIb

or pharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof,wherein:

R¹ and R² are each independently selected from hydrogen or halogen;

R³ is hydrogen or alkyl;

each Q¹ is independently deuterium, halo, cyano, oxo, thioxo, alkyl,haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w), ═NOR^(d), or —C(═NR^(y))N(R^(y))OR^(x),where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q³ groups, in one embodiment, one to threeQ³ groups; each Q³ is independently selected from deuterium, halo,hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NH;

each W is independently CR⁸ or N;

R⁸ is hydrogen, halo, haloalkyl or alkyl;

W¹ is N or C;

W² is N or CR^(9b);

R^(9b) is hydrogen or alkyl;

W⁴ is N or CR^(11b);

W⁵ is N or CR¹³;

R^(11b) and R¹³ are each independently hydrogen or Q²;

Q² is halo, deuterium, cyano, oxo, thioxo, alkyl, haloalkyl,haloalkenyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)OR^(x), —R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)),—R^(u)SR^(x), —R^(u)C(J)R^(x), —R^(u)C(J)OR^(x),—R^(u)C(J)N(R^(y))(R^(z)), —R^(u)C(J)R^(u)N(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —C(═NOR^(x))R^(x), —R^(u)S(O)_(t)R^(w),—R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w) or —C(═NR^(y))N(R^(y))OR^(x), where thealkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more groups Q⁴; in one embodiment, one to threeQ⁴ groups, each Q⁴ is independently selected from halo, deuterium,hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

Q⁵ and Q⁶ are each independently hydrogen, deuterium, halo, cyano, oxo,thioxo, alkyl, haloalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl,aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl,—R^(u)OR^(x), —R^(u)OR^(u)OR^(x), —R^(u)OR^(u)N(R^(y))(R^(z)),—R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x), —R^(u)C(J)R^(x), —R^(u)C(J)OR^(x),—R^(u)C(J)N(R^(y))(R^(z)), —R^(u)C(J)R^(u)N(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —C(═NOR^(x))R^(x), —R^(u)S(O)_(t)R^(w),—R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w) or —C(═NR^(y))N(R^(y))OR^(x), where thealkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q⁸ groups; each Q⁸ is independentlyselected from halo, deuterium, hydroxyl, alkyl, haloalkyl andhydroxyalkyl;

each R^(d) is independently hydrogen or alkyl;

each R^(u) is independently alkylene, alkenylene or a direct bond;

R^(w) is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl;

each R^(x) is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl;

R^(y) and R^(z) are each independently selected from (i) or (ii) below:

-   -   (i) R^(y) and R^(z) are each independently hydrogen, alkyl,        haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl,        cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl,        heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or        heteroaralkyl; or    -   (ii) R^(y) and R^(z), together with the nitrogen atom to which        they are attached, form a heterocyclyl or heteroaryl, optionally        substituted with one or more, in one embodiment, one, two or        three Q⁷ groups; each Q⁷ is independently selected from halo,        deuterium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl,        hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,        cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl,        heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2;

n is 1 or 2; and

q is an integer from 0-4.

In certain embodiment, provided herein are compounds of Formula VIIbwherein each Q¹ is independently halo, oxo, alkyl, haloalkyl,hydroxyalkyl, cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x); eachR^(u) is independently alkylene or a direct bond; each R^(x) isindependently hydrogen or alkyl; and the other variables are asdescribed elsewhere herein.

In certain embodiments, provided herein are compounds of Formula VIIbwherein R¹ and R² are both hydrogen. In certain embodiments, providedherein are compounds of Formula VIIb wherein Q⁵ and Q⁶ are eachindependently hydrogen, deuterium, halo, cyano, alkyl, alkenyl, alkynyl,cycloalkyl, alkoxy or alkylcarbonyl, and the other variables are asdescribed elsewhere herein. In certain embodiments, provided herein arecompounds of Formula VIIb, wherein Q⁵ is hydrogen and Q⁶ is halo,deuterium, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy oralkylcarbonyl. In certain embodiments, provided herein are compounds ofFormula VIIb, wherein Q⁵ is hydrogen and Q⁶ is halo, alkyl, alkenyl,alkynyl, cycloalkyl, alkoxy or alkylcarbonyl. In certain embodiments,provided herein are compounds of Formula VIIb, wherein Q⁵ is hydrogenand Q⁶ is halo, cyano, cycloalkyl, alkoxy or alkylcarbonyl. In certainembodiments, provided herein are compounds of Formula VIIb, wherein Q⁵is hydrogen and Q⁶ is bromo, chloro, fluoro, cyano, cyclopropyl, methoxyor methylcarbonyl.

In certain embodiments, provided herein are compounds of Formula VIII

or pharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereofwherein:

R¹ and R² are each independently selected from hydrogen or halogen;

R³ is hydrogen or alkyl;

each Q¹ is independently deuterium, halo, cyano, oxo, thioxo, alkyl,haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w), ═NOR^(d), or —C(═NR^(y))N(R^(y))OR^(x),where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q³ groups, in one embodiment, one to threeQ³ groups; each Q³ is independently selected from deuterium, halo,hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NH;

each W is independently CR⁸ or N;

R⁸ is hydrogen, halo, haloalkyl or alkyl;

ring A is aryl or heteroaryl, optionally substituted with one to foursubstituents selected from Q²;

W¹ is N or C;

W² is N, NR^(9a) or CR^(9b);

W³ is N, NR^(10a) or CR^(10b);

W⁴ is N, NR^(11a) or CR^(11b);

R^(9a), R^(9b), R^(10a), R^(10b), R^(11a) and R^(11b) are selected asfollows:

-   -   i) R^(9a), R^(10a) and R^(11a) are each independently hydrogen        or alkyl and R^(9b), R^(10b) and R^(11b) are each independently        hydrogen or Q²; or    -   ii) R^(9a) and R^(10b), R^(9b) and R^(10b), R^(9b) and R^(10a),        R^(10b) and R^(11a), R^(10a) and R^(11b) or R^(10b) and R^(11b),        together with the atoms to which they are attached form an aryl,        heteroaryl ring, wherein the aryl, heteroaryl ring is optionally        substituted with one or more, in one embodiment, one to three,        in another embodiment, one, two or three groups selected from        Q²; and the remainder of R^(9a) or R^(11a) is hydrogen or alkyl        and the remainder of R^(9b) or R^(11b) is hydrogen or Q²;

each Q² is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl,aminoalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)OR^(x), —R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)),—R^(u)SR^(x), —R^(u)C(J)R^(x), —R^(u)C(J)OR^(x),—R^(u)C(J)N(R^(y))(R^(z)), —R^(u)C(J)R^(u)N(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —C(═NOR^(x))R^(x), —R^(u)S(O)_(t)R^(w),—R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w) or —C(═NR^(y))N(R^(y))OR^(x), where thealkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q⁴ groups; each Q⁴ is independentlyselected from halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

each R^(d) is independently hydrogen or alkyl;

each R^(u) is independently alkylene, alkenylene or a direct bond;

R^(w) is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl;

each R^(x) is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl;

R^(y) and R^(z) are each independently selected from (i) or (ii) below:

-   -   (i) R^(y) and R^(z) are each independently hydrogen, alkyl,        haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl,        cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl,        heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or        heteroaralkyl; or    -   (ii) R^(y) and R^(z), together with the nitrogen atom to which        they are attached, form a heterocyclyl or heteroaryl, optionally        substituted with one or more, in one embodiment, one, two or        three Q⁷ groups; each Q⁷ is independently selected from halo,        deuterium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl,        hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,        cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl,        heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2;

n is 1 or 2; and

q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula VIIa,VIIb or VIII, wherein:

R¹ and R² are each hydrogen;

R³ is hydrogen or alkyl;

each Q¹ is independently halo, oxo, alkyl, hydroxyl, alkoxy, haloalkyl,hydroxyalkyl, cycloalkyl, ═NOH, or —R^(u)C(O)R^(x);

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NH;

each W is CH;

ring A is aryl or heteroaryl, optionally substituted with one to foursubstituents selected from Q²;

W¹ is N or C;

W² is N, NR^(9a) or CR^(9b);

W³ is N, NR^(10a) or CR^(10b);

W⁴ is N, NR^(11a) or CR^(11b);

R^(9a), R^(9b), R^(10a), R^(10b), R^(11a) and R^(11b) are selected asfollows:

-   -   i) R^(9a), R^(10a) and R^(11a) are each independently hydrogen        or alkyl and R^(9b), R^(10b) and R^(11b) are each independently        hydrogen, oxo, hydroxyl, halo or alkyl; or    -   ii) R^(9a) and R^(10b), R^(9b) and R^(10b), R^(9b) and R^(10a),        R^(10b) and R^(11a), R^(10a) and R^(11b) or R^(10b) and R^(11b),        together with the atoms to which they are attached form an aryl,        heteroaryl or heterocyclyl ring, wherein the aryl, heteroaryl or        heterocyclyl ring is optionally substituted with one or more, in        one embodiment, one to three, in another embodiment, one, two or        three groups selected from Q²; and the remainder of R^(9a),        R^(10a) or R^(11a) is hydrogen or alkyl or the remainder of        R^(9b), R^(10b) or R^(11b) is hydrogen, halo or alkyl;

each Q² is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl,aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w) or —C(═NR^(y))N(R^(y))OR^(x), where thealkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q⁴ groups; each Q⁴ is independentlyselected from halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

each R^(u) is independently alkylene or a direct bond;

R^(w) is alkyl;

each R^(x) is independently hydrogen or alkyl;

R^(y) and R^(z) are each independently hydrogen or alkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2;

n is 1 or 2; and

q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula VIII

or pharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereofwherein:

R¹ and R² are each independently selected from hydrogen or halogen;

R³ is hydrogen or alkyl;

each Q¹ is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl,cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x);

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NH;

each W is independently CR⁸ or N;

R⁸ is hydrogen, halo, haloalkyl or alkyl;

ring A is aryl or heteroaryl, optionally substituted with one to foursubstituents selected from Q²;

W¹ is N or C;

W² is N, NR^(9a) or CR^(9b);

W³ is N, NR^(10a) or CR^(10b);

W⁴ is N, NR^(11a) or CR^(11b);

R^(9a), R^(9b), R^(10a), R^(10b), R^(11a) and R^(11b) are selected asfollows:

-   -   i) R^(9a), R^(10a) and R^(11a) are each independently hydrogen        or alkyl and R^(9b), R^(10b) and R^(11b) are each independently        hydrogen, oxo, hydroxyl, halo or alkyl; or    -   ii) R^(9a) and R^(10b), R^(9b) and R^(10b), R^(9b) and R^(10a),        R^(10b) and R^(11a), R^(10a) and R^(11b) or R^(10b) and R^(11b),        together with the atoms to which they are attached form an aryl,        heteroaryl ring, wherein the aryl, heteroaryl ring is optionally        substituted with one or more, in one embodiment, one to three,        in another embodiment, one, two or three groups selected from        Q²; and the remainder of R^(9a), R^(10a) or R^(11a) is hydrogen        or alkyl or the remainder of R^(9b), R^(10b) or R^(11b) is        hydrogen, halo or alkyl;

each Q² is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl,aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w) or —C(═NR^(y))N(R^(y))OR^(x), where thealkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q⁴ groups; each Q⁴ is independentlyselected from halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

each R^(u) is independently alkylene or a direct bond;

R^(w) is alkyl;

each R^(x) is independently hydrogen or alkyl;

R^(y) and R^(z) are each independently hydrogen or alkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2;

n is 1 or 2; and

q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula VIIa,VIIb or VIII, wherein:

R¹ and R² are each hydrogen;

R³ is hydrogen or alkyl;

each Q¹ is independently halo, oxo, alkyl, hydroxyl, alkoxy, haloalkyl,hydroxyalkyl, cycloalkyl, ═NOH, or —R^(u)C(O)R^(x);

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NH;

each W is CH;

ring A is aryl or heteroaryl, optionally substituted with one to foursubstituents selected from Q²;

W¹ is N or C;

W² is N, NR^(9a) or CR^(9b);

W³ is N, NR^(10a) or CR^(10b);

W⁴ is N, NR^(11a) or CR^(11b);

R^(9a), R^(9b), R^(10a), R^(10b), R^(11a) and R^(11b) are selected asfollows:

-   -   i) R^(9a), R^(10a) and R^(11a) are each independently hydrogen        or alkyl and R^(9b), R^(10b) and R^(11b) are each independently        hydrogen, oxo, hydroxyl, halo or alkyl; or    -   ii) R^(9a) and R^(10b), R^(9b) and R^(10b), R^(9b) and R^(10a),        R^(10b) and R^(11a), R^(10a) and R^(11b) or R^(10b) and R^(11b),        together with the atoms to which they are attached form an aryl,        heteroaryl or heterocyclyl ring, wherein the aryl, heteroaryl or        heterocyclyl ring is optionally substituted with one or more, in        one embodiment, one to three, in another embodiment, one, two or        three groups selected from Q²; and the remainder of R^(9a),        R^(10a) or R^(11a) is hydrogen or alkyl or the remainder of        R^(9b), R^(10b) or R^(11b) is hydrogen, halo or alkyl;

each Q² is independently halo, cyano, oxo, thioxo, alkyl, haloalkyl,aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,cycloalkenylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w) or —C(═NR^(y))N(R^(y))OR^(x), where thealkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q⁴ groups; each Q⁴ is independentlyselected from halo, hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

each R^(u) is independently alkylene or a direct bond;

R^(w) is alkyl;

each R^(x) is independently hydrogen or alkyl;

R^(y) and R^(z) are each independently hydrogen or alkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2;

n is 1 or 2; and

q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula VIIIwherein each Q¹ is independently halo, oxo, alkyl, haloalkyl,hydroxyalkyl, cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x); eachR^(u) is independently alkylene or a direct bond; each R^(x) isindependently hydrogen or alkyl; and the other variables are asdescribed elsewhere herein.

In certain embodiments, provided herein are compounds of Formula IX

or pharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof,wherein:

R³ is hydrogen or alkyl;

each Q¹ is independently deuterium, halo, cyano, oxo, thioxo, alkyl,haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w), ═NOR^(d), or —C(═NR^(y))N(R^(y))OR^(x),where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q³ groups, in one embodiment, one to threeQ³ groups; each Q³ is independently selected from deuterium, halo,hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NH;

W⁴ is N or CR^(11b);

W⁵ is N or CR¹³;

R^(11b) and R¹³ are each independently hydrogen or Q²;

each Q² is independently halo, deuterium, cyano, oxo, thioxo, alkyl,haloalkyl, haloalkenyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl,—R^(u)OR^(x), —R^(u)OR^(u)OR^(x), —R^(u)OR^(u)N(R^(y))(R^(z)),—R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x), —R^(u)C(J)R^(x), —R^(u)C(J)OR^(x),—R^(u)C(J)N(R^(y))(R^(z)), —R^(u)C(J)RN(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —C(═NOR^(x))R^(x), —R^(u)S(O)_(t)R^(w),—R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w) or —C(═NR^(y))N(R^(y))OR^(x), where thealkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more groups Q⁴; in one embodiment, one to threeQ⁴ groups, each Q⁴ is independently selected from halo, deuterium,hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

Q⁵ and Q⁶ are each independently hydrogen, halo, cyano, alkyl,haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x), —R^(u)C(J)R^(x), —R^(u)C(J)OR^(x),—R^(u)C(J)N(R^(y))(R^(z)), —R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x),—R^(u)N(R^(x))C(J)OR^(x), —R^(u)N(R^(x))S(O)_(t)R^(w) or—C(═NR^(y))N(R^(y))OR^(x), where the alkyl, haloalkyl, aminoalkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, andheterocyclyl groups are optionally substituted with one or more Q⁸groups; each Q⁸ is independently selected from halo, deuterium,hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

R^(d) is hydrogen or alkyl;

each R^(u) is independently alkylene, alkenylene or a direct bond;

R^(w) is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl;

each R^(x) is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl;

R^(y) and R^(z) are each independently selected from (i) or (ii) below:

-   -   (i) R^(y) and R^(z) are each independently hydrogen, alkyl,        haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl,        cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl,        heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or        heteroaralkyl; or    -   (ii) R^(y) and R^(z), together with the nitrogen atom to which        they are attached, form a heterocyclyl or heteroaryl, optionally        substituted with one or more, in one embodiment, one, two or        three Q⁷ groups; each Q⁷ is independently selected from halo,        deuterium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl,        hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,        cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl,        heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2;

n is 1 or 2; and

q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula IX orpharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof, wherein:

R³ is hydrogen or alkyl;

each Q¹ is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl,cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x);

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NH;

W⁴ is N or CR^(11b);

R^(11b) is hydrogen, halo or alkyl;

W⁵ is N or CR¹³;

R¹³ is hydrogen, halo or alkyl;

Q⁵ and Q⁶ are each independently hydrogen, halo, cyano, alkyl,haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x), —R^(u)C(J)R^(x), —R^(u)C(J)OR^(x),—R^(u)C(J)N(R^(y))(R^(z)), —R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x),—R^(u)N(R^(x))C(J)OR^(x), —R^(u)N(R^(x))S(O)_(t)R^(w) or—C(═NR^(y))N(R^(y))OR^(x), where the alkyl, haloalkyl, aminoalkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, andheterocyclyl groups are optionally substituted with one or more Q⁸groups; each Q⁸ is independently selected from halo, deuterium,hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

each R^(u) is independently alkylene or a direct bond;

R^(w) is alkyl;

each R^(x) is independently hydrogen or alkyl;

R^(y) and R^(z) are each independently hydrogen or alkyl;

J is O, NR^(x) or S;

each t is independently an integer from 0-2;

n is 1 or 2; and

q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula IXwherein each Q¹ is independently halo, oxo, alkyl, haloalkyl,hydroxyalkyl, cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x); eachR^(u) is independently alkylene or a direct bond; each R^(x) isindependently hydrogen or alkyl; R^(11b) and R¹³ are each independentlyhydrogen, halo or alkyl; and the other variables are as describedelsewhere herein. In certain embodiments, provided herein are compoundsof Formula IX, wherein Q⁵ and Q⁶ are each independently hydrogen, halo,alkoxy, tetrazole or pyrazole, where the tetrazole and pyrazole ringsare optionally substituted with one or more alkyl, and the othervariables are as described elsewhere herein. In certain embodiments, Q⁵and Q⁶ are each independently hydrogen, chloro, fluoro, bromo ormethoxy, and the other variables are as described elsewhere herein.

In certain embodiments, provided herein are compounds of Formula X

or pharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof,wherein:

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, aryl, heterocyclyl or heteroaryl, where R⁴ isoptionally substituted with one or more, in one embodiment, one tothree, in another embodiment, one, two or three groups selected from Q¹;

each Q¹ is independently deuterium, halo, cyano, oxo, thioxo, alkyl,haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w), ═NOR^(d), or —C(═NR^(y))N(R^(y))OR^(x),where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q³ groups, in one embodiment, one to threeQ³ groups; each Q³ is independently selected from deuterium, halo,hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

each R^(d) is independently hydrogen or alkyl;

each R^(u) is independently alkylene, alkenylene or a direct bond;

R^(w) is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl;

each R^(x) is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl;

R^(y) and R^(z) are each independently selected from (i) or (ii) below:

-   -   (i) R^(y) and R^(z) are each independently hydrogen, alkyl,        haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl,        cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl,        heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or        heteroaralkyl; or    -   (ii) R^(y) and R^(z), together with the nitrogen atom to which        they are attached, form a heterocyclyl or heteroaryl, optionally        substituted with one or more, in one embodiment, one, two or        three Q⁷ groups; each Q⁷ is independently selected from halo,        deuterium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl,        hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,        cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl,        heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl;

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NH;

W⁴ is N or CR^(11b);

R^(11b) is hydrogen or Q²;

Q² is halo, deuterium, cyano, oxo, thioxo, alkyl, haloalkyl,haloalkenyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)OR^(x), —R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)),—R^(u)SR^(x), —R^(u)C(J)R^(x), —R^(u)C(J)OR^(x),—R^(u)C(J)N(R^(y))(R^(z)), —R^(u)C(J)RN(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —C(═NOR^(x))R^(x), —R^(u)S(O)_(t)R^(w),—R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w) or —C═(NR^(y))N(R^(y))OR^(x), where thealkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more groups Q⁴; in one embodiment, one to threeQ⁴ groups, each Q⁴ is independently selected from halo, deuterium,hydroxyl, alkyl, haloalkyl and hydroxyalkyl;

W⁵ is N or CR¹³;

R¹³ is hydrogen, halo or alkyl; and

q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula Xwherein each Q¹ is independently halo, oxo, alkyl, haloalkyl,hydroxyalkyl, cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x); eachR^(u) is independently alkylene or a direct bond; each R^(x) isindependently hydrogen or alkyl; and the other variables are asdescribed elsewhere herein.

In certain embodiments, provided herein are compounds of Formula X orpharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof, wherein:

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, aryl, heterocyclyl or heteroaryl, where R⁴ isoptionally substituted with one or more, in one embodiment, one tothree, in another embodiment, one, two or three groups selected from Q¹;

each Q¹ is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl,cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x);

each R^(u) is independently alkylene or a direct bond;

each R^(x) is independently hydrogen or alkyl;

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NH;

W⁴ is N or CR^(11b);

R^(11b) is hydrogen, halo or alkyl;

W⁵ is N or CR¹³;

R¹³ is hydrogen, halo or alkyl; and

q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula XI

or pharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof,wherein:

R³ is hydrogen or alkyl;

each Q¹ is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl,cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x);

each R^(u) is independently alkylene or a direct bond;

each R^(x) is independently hydrogen or alkyl;

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NH;

W⁴ is N or CR^(11b);

R^(11b) is hydrogen, halo or alkyl;

W⁵ is N or CR¹³;

R¹³ is hydrogen, halo or alkyl; and

q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula XI orpharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof, wherein:

R³ is hydrogen or alkyl;

each Q¹ is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl,cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x);

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NH;

W⁴ is N or CR^(11b);

R^(11b) is hydrogen, halo or alkyl;

W⁵ is N or CR¹³;

R¹³ is hydrogen, halo or alkyl; and

q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula XII

or pharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof,wherein:

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, aryl, heterocyclyl or heteroaryl, where R⁴ isoptionally substituted with one or more, in one embodiment, one tothree, in another embodiment, one, two or three groups selected from Q¹;

each Q¹ is independently halo, oxo, alkyl, haloalkyl, hydroxyalkyl,cycloalkyl, ═NOH, —R^(u)OR^(x) or —R^(u)C(O)R^(x);

each R^(u) is independently alkylene or a direct bond;

each R^(x) is independently hydrogen or alkyl;

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NH;

R^(11a) is hydrogen or alkyl;

W⁶ is N or CR¹⁴;

R¹⁴ is hydrogen or alkyl;

a is 0-4; and

q is an integer from 0-4.

In certain embodiments, provided herein are compounds of Formula XII orpharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers thereof, wherein:

R³ is hydrogen or alkyl;

R⁴ is cycloalkyl, where R⁴ is optionally substituted with hydroxy;

Y is —(CR⁵R⁶)_(q)—;

R⁵ and R⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl;

Z is O, S, or NH;

R^(11a) is hydrogen or alkyl;

W⁶ is N or CR¹⁴;

R¹⁴ is hydrogen or alkyl;

a is 0-2; and

q is an integer from 0-2.

In one embodiment, the compound provided herein is selected from:

-   2-((6-((1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   (1R,2R)-2-((6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   (1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol    methanesulfonic acid,-   (1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol-   2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol-   (1R,2R)-2-((6-((6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   (1R,2R)-2-((6-((5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   (1R,2R)-2-((6-((1H-imidazo[4,5-b]pyridin-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((1H-imidazo[4,5-b]pyridin-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   (1R,2R)-2-((6-((1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((1H-imidazo[4,5-b]pyridin-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   (1    S,2S)-2-((6-((1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   (R)-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-N-((tetrahydrofuran-2-yl)methyl)benzo[d]thiazol-2-amine,-   6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-N-((tetrahydrofuran-2-yl)methyl)benzo[d]thiazol-2-amine,-   6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-N-(pyridin-2-ylmethyl)benzo[d]thiazol-2-amine,-   (1R,2S)-1-((6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol,-   1-((6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol,-   (S)—N-(2,3-dihydro-1H-inden-1-yl)-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-amine,-   N-(2,3-dihydro-1H-inden-1-yl)-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-amine,-   (1R,2R)-2-((6-(methoxy(1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-(methoxy(1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   N-benzyl-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-amine,-   6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-N-(2-morpholinoethyl)benzo[d]thiazol-2-amine,-   6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazol-2-amine,-   N-cyclohexyl-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-N-methylbenzo[d]thiazol-2-amine,-   (1R,2R)-2-((6-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   N-cyclohexyl-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-amine,-   (1R,2R)-1-((6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol,-   1-((6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol,-   (1R,2R)-2-((6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclopentanol,-   2-((6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclopentanol,-   6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-N-(pyridin-4-ylmethyl)benzo[d]thiazol-2-amine,-   6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-N-phenylbenzo[d]thiazol-2-amine,-   (1R,2R)-2-((6-((5-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((5-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   1-(4-((6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)piperidin-1-yl)ethanone    acetic acid,-   1-(4-((6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)piperidin-1-yl)ethanone,-   (R,S)-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-N-(tetrahydrofuran-3-yl)benzo[d]thiazol-2-amine    acetic acid,-   (R,S)-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-N-(tetrahydrofuran-3-yl)benzo[d]thiazol-2-amine,-   6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-N-(tetrahydrofuran-3-yl)benzo[d]thiazol-2-amine,-   3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-2-aminium    acetate,-   (1R,2R)-2-((6-((2-amino-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((2-amino-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-N-(2-ethoxyphenyl)benzo[d]thiazol-2-amine,-   N-(cyclohexylmethyl)-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-amine,-   (1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-N-(2-methoxyphenyl)benzo[d]thiazol-2-amine,-   2-((6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)phenol,-   (1R,2R)-1-((6-((4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol,-   1-((6-((4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol,-   (1R,2R)-1-((6-((5-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol,-   1-((6-((5-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol,-   (S)—N-(1-cyclohexylethyl)-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-amine,-   N-(1-cyclohexylethyl)-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-amine,-   (1R,2R)-2-((6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol,-   2-((6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol,-   N-(cyclohexylmethyl)-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]oxazol-2-amine,-   (1R,2R)-2-((6-((4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-N-methyl-1H-imidazole-4-carboxamide,-   1-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-N-methyl-1    H-imidazole-4-carboxamide-   (1R,2R)-2-((6-(imidazo[1,2-a]pyridin-3-ylmethyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-(imidazo[1,2-a]pyridin-3-ylmethyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   (1R,2R)-2-((6-((6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   (1R,2R)-2-((6-((6-(pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((6-(pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   (1R,2R)-2-((6-((5-bromo-6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((5-bromo-6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   (1R,2R)-1-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol,-   1-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol,-   3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile,-   3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile,-   (1R,2R)-2-((6-((7-methoxyimidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((7-methoxyimidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   (1R,2R)-2-((6-((6-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((6-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   (1R,2R)-1-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol,-   1-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol,-   (1R,2R)-2-((6-((6-bromo-5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((6-bromo-5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   (1R,2R)-2-((6-((9H-purin-9-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((9H-purin-9-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   (1R,2R)-1-((6-((5-bromo-6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol,-   1-((6-((5-bromo-6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol,-   (±)-(1R,2R)(1S,2S)-2-((6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cycloheptanol,-   2-((6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cycloheptanol,-   (1R,2R)-2-((6-((6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   (1R,2R)-2-((6-((5-methoxy-6-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((5-methoxy-6-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-5-methoxy-1H-benzo[d]imidazole-6-carbonitrile,-   1-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-5-methoxy-1H-benzo[d]imidazole-6-carbonitrile,-   (R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanone,-   2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanone,-   (1R,2R)-2-((6-((6-chloro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((6-chloro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   (1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol,-   2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol,-   (1R,2R)-1-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]oxazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol,-   1-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]oxazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol,-   (R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanone    oxime,-   2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanone    oxime,-   (1S,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-1-methylcyclohexanol,-   (1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-1-methylcyclohexanol,-   2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-1-methylcyclohexanol,-   (1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol,-   2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol,-   (1R,2R)-1-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]oxazol-2-yl)amino)-2,    3-dihydro-1H-inden-2-ol,-   1-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]oxazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol,-   (S)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-2-cyclohexylethanol,-   2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-2-cyclohexylethanol,-   (R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-2-cyclohexylethanol,-   1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-6-methoxy-1H-benzo[d]imidazole-5-carbonitrile,-   1-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-6-methoxy-1H-benzo[d]imidazole-5-carbonitrile,-   ((1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)methanol,-   2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)methanol,-   (1R,2R)-2-((6-((6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   (1R,2R)-2-((6-((5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   (1R,2R)-1-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol,-   1-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol,-   (1R,2R)-2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   (1R,2R)-2-((6-((3H-imidazo[4,5-c]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((3H-imidazo[4,5-c]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   (1R,2R)-2-((6-((1H-imidazo[4,5-c]pyridin-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((1H-imidazo[4,5-c]pyridin-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)ethanone,-   1-(3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)ethanone,-   (1R,2R)-2-((6-((6-(methyl    sulfonyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((6-(methylsulfonyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   1-(((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)methyl)cyclohexanol,-   (1-(((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)methyl)cyclohexyl)methanol,-   (1R,2R)-2-((6-((4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol,-   2-((6-((4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol,-   (1R,2R)-2-((6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   methyl    3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate,-   methyl    3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyri    dine-6-carboxylate,-   (1R,2R)-1-((6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol,-   1-((6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol,-   3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylic    acid,-   3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylic    acid,-   (1R,2R)-2-((6-((6-(morpholinomethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((6-(morpholinomethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   (1R,2R)-2-((6-((6-(hydroxymethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((6-(hydroxymethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   (1R,2R)-2-((6-((6-(methylthio)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((6-(methylthio)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   (1R,2R)-2-((6-((6-((methylthio)methyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((6-((methylthio)methyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile,-   3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyri    dine-5-carbonitrile,-   1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)ethanone,-   1-(3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)ethanone,-   3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-N-methyl-3H-imidazo[4,5-b]pyridine-6-carboxamide,-   3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-N-methyl-3H-imidazo[4,5-b]pyridine-6-carboxamide,-   N-hydroxy-3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboximidamide,-   (1R,2R)-2-((6-((6-(aminomethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol    acetic acid,-   (1R,2R)-2-((6-((6-(aminomethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((6-(aminomethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-N,N-dimethyl-3H-imidazo[4,5-b]pyridine-6-carboxamide,-   3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-N,N-dimethyl-3H-imidazo[4,5-b]pyridine-6-carboxamide,-   (1R,2R)-2-((6-((6-(2H-tetrazol-5-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((6-(2H-tetrazol-5-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   (1R,2R)-2-((6-((6-(2-methyl-2H-tetrazol-5-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((6-(2-methyl-2H-tetrazol-5-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   (1R,2R)-2-((6-((6-(1-methyl-1H-tetrazol-5-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((6-(1-methyl-1H-tetrazol-5-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   (1R,2R)-1-((6-((9H-purin-9-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol,-   1-((6-((9H-purin-9-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol,-   (1R,2R)-2-((6-((6-ethynyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((6-ethynyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   (1R,2R)-2-((6-((6-morpholino-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((6-morpholino-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   (1R,2R)-2-((6-((6-vinyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((6-vinyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   N-((3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)methyl)acetamide,-   N-((3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)methyl)acetamide,-   (1R,2R)-2-((6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   N-(1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-imidazol-4-yl)acetamide,-   N-(1-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-imidazol-4-yl)acetamide,-   (1R,2R)-2-((6-((6-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   2-((6-((6-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol,-   1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3-(1-methyl-1H-pyrazol-4-yl)pyrazin-2(1H)-one,    and-   1-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3-(1-methyl-1H-pyrazol-4-yl)pyrazin-2(1H)-one.

In one embodiment, the compound provided herein is selected from:

-   (1R,2R)-2-((6-((6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((2-(trifluoromethyl)-9H-purin-9-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((2-(trifluoromethyl)-9H-purin-9-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((5-(methylsulfonyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((5-(methylsulfonyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((6-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((6-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;-   1-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;-   (1R,2R)-2-((6-((6-(2-hydroxypropan-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((6-(2-hydroxypropan-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   1-(1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)ethanone;-   1-(1-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)ethanone;-   1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile;-   1-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile;-   (1R,2R)-2-((6-((5-(methylsulfonyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((5-(methylsulfonyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((6-(methylsulfonyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((6-(methylsulfonyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)thiazolo[4,5-b]pyridin-2-yl)amino)cyclohexanol;-   2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)thiazolo[4,5-b]pyridin-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((6-((R,S)-1-hydroxyethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((6-(1-hydroxyethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-(dimethylamino)-1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)ethanone    acetate salt;-   2-(dimethylamino)-1-(3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)ethanone;-   2-(dimethylamino)-1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)ethanone;-   3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridine-7-carbonitrile;-   3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridine-7-carbonitrile;-   (1R,2R)-2-((6-((9H-purin-9-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol;-   2-((6-((9H-purin-9-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((5,6-dimethyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((5,6-dimethyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   1-(1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-6-yl)ethanone;-   1-(1-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-6-yl)ethanone;-   (1R,2R)-2-((6-((5-ethynyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((5-ethynyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((6-ethynyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((6-ethynyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((6-bromo-5-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((6-bromo-5-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]oxazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile;-   3-((2-((2-hydroxycyclohexyl)amino)benzo[d]oxazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile;-   (1R,2R)-2-((6-(imidazo[1,2-a]pyrazin-3-ylmethyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-(imidazo[1,2-a]pyrazin-3-ylmethyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-5-methoxy-3H-imidazo[4,5-b]pyridine-6-carbonitrile;-   3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-5-methoxy-3H-imidazo[4,5-b]pyridine-6-carbonitrile;-   (1R,2R)-2-((6-((5-methyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((5-methyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((5,6-difluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((5,6-difluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-(imidazo[1,2-b]pyridazin-3-ylmethyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-(imidazo[1,2-b]pyridazin-3-ylmethyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol;-   2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol;-   ((1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)methanol;-   2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)methanol;-   (1R,2R)-2-((6-((6-(1-methyl-1H-tetrazol-5-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((6-(1-methyl-1H-tetrazol-5-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((7-(2-hydroxyethoxy)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((7-(2-hydroxyethoxy)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   ((1S,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)methanol;-   2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)methanol;-   (1R,2R)-2-((6-((5,6-dichloro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((5,6-dichloro-3H-imidazo[4,5-b]pyri    din-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((5-ethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((5-ethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-5,6-dicarbonitrile;-   3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyri    dine-5,6-dicarbonitrile;-   3-((2-(((1R,2R)-2-(hydroxymethyl)cyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile;-   3-((2-((2-(hydroxymethyl)cyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile;-   (1R,2R)-2-((6-((6-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((6-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-(imidazo[1,2-b]pyridazin-3-ylmethyl)benzo[d]oxazol-2-yl)amino)cyclohexanol;-   2-((6-(imidazo[1,2-b]pyridazin-3-ylmethyl)benzo[d]oxazol-2-yl)amino)cyclohexanol;-   3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-N-methylimidazo[1,2-b]pyridazine-6-carboxamide;-   3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-N-methylimidazo[1,2-b]pyridazine-6-carboxamide;-   (1R,2R)-2-((6-((6-(hydroxymethyl)imidazo[1,2-b]pyridazin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((6-(hydroxymethyl)imidazo[1,2-b]pyridazin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((6-(1H-1,2,4-triazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((6-(1H-1,2,4-triazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((6-iodo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((6-iodo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-ol;-   1-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-ol;-   (1R,2R)-2-((6-((5,7-difluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((5,7-difluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((5-(trifluoromethoxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((5-(trifluoromethoxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((6-methoxyimidazo[1,2-b]pyridazin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((6-methoxyimidazo[1,2-b]pyridazin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol;-   2-((6-((5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol;-   2-((6-((6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-fluorobenzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-fluorobenzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((6-morpholinoimidazo[1,2-b]pyridazin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((6-morpholinoimidazo[1,2-b]pyridazin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((4-chloro-6-((6-morpholinoimidazo[1,2-b]pyridazin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((4-chloro-6-((6-morpholinoimidazo[1,2-b]pyridazin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-(imidazo[2,    1-b]thiazol-5-ylmethyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-(imidazo[2,    1-b]thiazol-5-ylmethyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((6-chloroimidazo[1,2-b]pyridazin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((6-chloroimidazo[1,2-b]pyridazin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((6-(1H-pyrazol-1-yl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((6-(1H-pyrazol-1-yl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((5-(1H-1,2,4-triazol-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((5-(1H-1,2,4-triazol-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1    S,2R)-2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   trans-4-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   4-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-7-fluorobenzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-7-fluorobenzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((6-methoxyimidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((6-methoxyimidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-4-bromobenzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-4-bromobenzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((7-(1H-pyrazol-1-yl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((7-(1H-pyrazol-1-yl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-4,7-difluorobenzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-4,7-difluorobenzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((7-(1H-1,2,4-triazol-1-yl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((7-(1H-1,2,4-triazol-1-yl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]oxazol-6-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;-   1-((2-((2-hydroxycyclohexyl)amino)benzo[d]oxazol-6-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;-   (1R,2R)-2-((6-((5-(2-morpholinoethoxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((5-(2-morpholinoethoxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((5-(2-hydroxyethoxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((5-(2-hydroxyethoxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-N-methyl-1H-benzo[d]imidazole-5-carboxamide;-   1-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-N-methyl-1    H-benzo[d]imidazole-5-carboxamide;-   (1R,2R)-2-((6-((5-(3,6-dihydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((5-(3,    6-dihydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((5-(3,3,3-trifluoroprop-1-en-2-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((5-(3,3,3-trifluoroprop-1-en-2-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (R)—N-(cyclohex-2-en-1-yl)-6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-amine;-   N-(cyclohex-2-en-1-yl)-6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-amine;-   (1R,2R)-2-((6-((6-bromoimidazo[1,2-b]pyridazin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((6-bromoimidazo[1,2-b]pyridazin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (trans-4-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)methanol;-   (cis-4-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)methanol;-   4-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)methanol;-   6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-N-((1R,2R)-2-(methylthio)cyclohexyl)benzo[d]thiazol-2-amine;-   6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-N-(2-(methylthio)cyclohexyl)benzo[d]thiazol-2-amine;-   (1R,2R)-2-((6-((5-(oxetan-3-yloxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((5-(oxetan-3-yloxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((5-vinyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((5-vinyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((5-(cyclohex-1-en-1-yl)-1H-benzo[d]imidazol-1-yl)-   methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((5-(cyclohex-1-en-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((5-fluoroimidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((5-fluoroimidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((7-morpholinoimidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((7-morpholinoimidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((7-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((7-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   ((1R,2R)-2-((6-((5,7-dimethyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((5,7-dimethyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((5-bromo-7-methyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((5-bromo-7-methyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-N-phenylbenzo[d]thiazol-2-amine;-   ((1R,3R)-3-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)methanol;-   3-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)methanol;-   (1R,2S,3R)-3-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol;-   3-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol;-   ((1S,3R)-3-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)methanol;-   3-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)methanol;-   6-chloro-1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]oxazol-6-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;-   6-chloro-1-((2-((2-hydroxycyclohexyl)amino)benzo[d]oxazol-6-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;-   2-((1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)oxy)acetonitrile;-   2-((1-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)oxy)acetonitrile;-   6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-N-(2-methoxyphenyl)benzo[d]thiazol-2-amine;-   N-((1R,2R)-2-chlorocyclohexyl)-6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-amine;-   N-(2-chlorocyclohexyl)-6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-amine;-   1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridin-7-yl)piperidin-4-ol;-   1-(3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridin-7-yl)piperidin-4-ol;-   1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridin-7-yl)ethanone;-   1-(3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridin-7-yl)ethanone;-   (1R,2R)-2-((6-((7-(1-hydroxyethyl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((7-(1-hydroxyethyl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridin-7-yl)ethanone    oxime;-   1-(3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridin-7-yl)ethanone    oxime;-   (1R,2R)-2-((6-((5-bromo-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((5-bromo-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridin-7-yl)ethanone    O-methyl oxime;-   1-(3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridin-7-yl)ethanone    O-methyl oxime;-   (1R,2R)-2-((6-((9H-benzo[d]imidazo[1,2-a]imidazol-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((9H-benzo[d]imidazo[1,2-a]imidazol-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   7-fluoro-1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;-   7-fluoro-1-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;-   (1R,2R)-2-((6-((7-fluoro-5-vinyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((7-fluoro-5-vinyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((5-(3,    6-dihydro-2H-pyran-4-yl)-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((5-(3,    6-dihydro-2H-pyran-4-yl)-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((5-morpholino-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((5-morpholino-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   1-(1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)piperidin-2-one;-   1-(1-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)piperidin-2-one;-   (1R,2R)-2-((6-((5-(1H-pyrazol-3-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((5-(1H-pyrazol-3-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1S,2S)-2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((7-(1H-imidazol-1-yl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((7-(1H-imidazol-1-yl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((7-(2H-1,2,3-triazol-2-yl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((7-(2H-1,2,3-triazol-2-yl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((7-vinylimidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((7-vinylimidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((7-(allyloxy)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((7-(allyloxy)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((7-(1H-1,2,3-triazol-1-yl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((7-(1H-1,2,3-triazol-1-yl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   N-((1R,2S)-2-chlorocyclohexyl)-6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-amine;-   N-(2-chlorocyclohexyl)-6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-amine;-   3-amino-1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)pyrazin-2(1H)-one    acetate salt;-   3-amino-1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)pyrazin-2(1H)-one;-   3-amino-1-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)pyrazin-2(1H)-one;-   3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-b]pyridazine-6-carbonitrile;-   3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-b]pyridazine-6-carbonitrile;-   1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3-morpholinopyrazin-2(1H)-one;-   1-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3-morpholinopyrazin-2(1H)-one;-   (3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridin-7-yl)(pyrrolidin-1-yl)methanone;-   (3-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridin-7-yl)(pyrrolidin-1-yl)methanone;-   (E)-3-(1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)acrylic    acid;-   (E)-3-(1-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)acrylic    acid;-   3-(1-((2-((2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)acrylic    acid;-   (1R,2R)-2-((6-((5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((5-(1,2,3,    6-tetrahydropyridin-4-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((5-(1H-imidazol-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((5-(1H-imidazol-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1R,2R)-2-((6-((5-(2-methyl-2H-tetrazol-5-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   2-((6-((5-(2-methyl-2H-tetrazol-5-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol;-   (1S,2R,3R)-3-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol;-   3-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol;-   (1R,2S,3R)-3-((6-((7-(1H-pyrazol-1-yl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol;-   3-((6-((7-(1H-pyrazol-1-yl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol;-   (1R,2S,3R)-3-((6-((5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol;-   3-((6-((5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol;-   (1R,2S,3R)-3-((6-((7-(2H-1,2,3-triazol-2-yl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol;-   3-((6-((7-(2H-1,2,3-triazol-2-yl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol;-   (1R,2S,3R)-3-((6-((5-vinyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol;-   3-((6-((5-vinyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol;-   (1R,2S,3R)-3-((6-((5-(oxetan-3-yloxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol;-   3-((6-((5-(oxetan-3-yloxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol;-   (1R,2S,3R)-3-((6-((6-(1H-1,2,4-triazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol;-   3-((6-((6-(1H-1,2,4-triazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol;-   (1R,2S,3R)-3-((6-((5-morpholino-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol;-   3-((6-((5-morpholino-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol;-   (1R,2S,3R)-3-((6-((5-(2-methyl-2H-tetrazol-5-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol;    and-   3-((6-((5-(2-methyl-2H-tetrazol-5-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol.

Also provided herein are isotopically enriched analogs of the compoundsprovided herein. Isotopic enrichment (for example, deuteration) ofpharmaceuticals to improve pharmacokinetics (“PK”), pharmacodynamics(“PD”), and toxicity profiles, has been demonstrated previously withsome classes of drugs. See, for example, Lijinsky et. al., Food Cosmet.Toxicol., 20: 393 (1982); Lijinsky et. al., J. Nat. Cancer Inst., 69:1127 (1982); Mangold et. al., Mutation Res. 308: 33 (1994); Gordon et.al., Drug Metab. Dispos., 15: 589 (1987); Zello et. al., Metabolism, 43:487 (1994); Gately et. al., J. Nucl. Med., 27: 388 (1986); Wade D, Chem.Biol. Interact. 117: 191 (1999).

Isotopic enrichment of a drug can be used, for example, to (1) reduce oreliminate unwanted metabolites, (2) increase the half-life of the parentdrug, (3) decrease the number of doses needed to achieve a desiredeffect, (4) decrease the amount of a dose necessary to achieve a desiredeffect, (5) increase the formation of active metabolites, if any areformed, and/or (6) decrease the production of deleterious metabolites inspecific tissues and/or create a more effective drug and/or a safer drugfor combination therapy, whether the combination therapy is intentionalor not.

Replacement of an atom for one of its isotopes often will result in achange in the reaction rate of a chemical reaction. This phenomenon isknown as the Kinetic Isotope Effect (“KIE”). For example, if a C—H bondis broken during a rate-determining step in a chemical reaction (i.e.the step with the highest transition state energy), substitution of adeuterium for that hydrogen will cause a decrease in the reaction rateand the process will slow down. This phenomenon is known as theDeuterium Kinetic Isotope Effect (“DKIE”). (See, e.g, Foster et al.,Adv. Drug Res., vol. 14, pp. 1-36 (1985); Kushner et al., Can. J.Physiol. Pharmacol., vol. 77, pp. 79-88 (1999)).

Tritium (“T”) is a radioactive isotope of hydrogen, used in research,fusion reactors, neutron generators and radiopharmaceuticals. Tritium isa hydrogen atom that has 2 neutrons in the nucleus and has an atomicweight close to 3. It occurs naturally in the environment in very lowconcentrations, most commonly found as T₂O. Tritium decays slowly(half-life=12.3 years) and emits a low energy beta particle that cannotpenetrate the outer layer of human skin. Internal exposure is the mainhazard associated with this isotope, yet it must be ingested in largeamounts to pose a significant health risk. As compared with deuterium, alesser amount of tritium must be consumed before it reaches a hazardouslevel. Substitution of tritium (“T”) for hydrogen results in yet astronger bond than deuterium and gives numerically larger isotopeeffects. Similarly, substitution of isotopes for other elements,including, but not limited to, ¹³C or ¹⁴C for carbon, ³³S, ³⁴S, or ³⁶Sfor sulfur, ¹⁵N for nitrogen, and ¹⁷O or ¹⁸O for oxygen, will provide asimilar kinetic isotope effects.

In another embodiment, provided herein are methods of using thedisclosed compounds and compositions, or pharmaceutically acceptablesalts, solvates, hydrates, clathrates, single stereoisomers, mixture ofstereoisomers or racemic mixture of stereoisomers thereof, for the localor systemic treatment or prophylaxis of human and veterinary diseases,disorders and conditions modulated or otherwise affected mediated viaCSF1R, FLT3, KIT, and/or PDGFRβ kinase activity.

C. FORMULATION OF PHARMACEUTICAL COMPOSITIONS

The pharmaceutical compositions provided herein contain therapeuticallyeffective amounts of one or more of compounds provided herein that areuseful in the prevention, treatment, or amelioration of CSF1R, FLT3,KIT, and/or PDGFRβ kinase mediated diseases or one or more of thesymptoms thereof.

The compositions contain one or more compounds provided herein. Thecompounds can be formulated into suitable pharmaceutical preparationssuch as solutions, suspensions, tablets, dispersible tablets, pills,capsules, powders, sustained release formulations or elixirs, for oraladministration or in sterile solutions or suspensions for parenteraladministration, as well as transdermal patch preparation and dry powderinhalers. Typically the compounds described above are formulated intopharmaceutical compositions using techniques and procedures well knownin the art.

In the compositions, effective concentrations of one or more compoundsor pharmaceutically acceptable salts, solvates, hydrates, clathrates,single stereoisomers, mixture of stereoisomers or racemic mixture ofstereoisomers or prodrug is (are) mixed with a suitable pharmaceuticalcarrier or vehicle. The concentrations of the compounds in thecompositions are effective for delivery of an amount, uponadministration, that treats, prevents, or ameliorates one or more of thesymptoms of CSF1R, FLT3, KIT, and/or PDGFRβ kinase mediated diseases.

Typically, the compositions are formulated for single dosageadministration. To formulate a composition, the weight fraction ofcompound is dissolved, suspended, dispersed or otherwise mixed in aselected vehicle at an effective concentration such that the treatedcondition is relieved or ameliorated. Pharmaceutical carriers orvehicles suitable for administration of the compounds provided hereininclude any such carriers known to those skilled in the art to besuitable for the particular mode of administration.

In addition, the compounds may be formulated as the solepharmaceutically active ingredient in the composition or may be combinedwith other active ingredients. Liposomal suspensions, includingtissue-targeted liposomes, such as tumor-targeted liposomes, may also besuitable as pharmaceutically acceptable carriers. These may be preparedaccording to methods known to those skilled in the art. For example,liposome formulations may be prepared as known in the art. Briefly,liposomes such as multilamellar vesicles (MLV's) may be formed by dryingdown egg phosphatidyl choline and brain phosphatidyl serine (7:3 molarratio) on the inside of a flask. A solution of a compound providedherein in phosphate buffered saline lacking divalent cations (PBS) isadded and the flask shaken until the lipid film is dispersed. Theresulting vesicles are washed to remove unencapsulated compound,pelleted by centrifugation, and then resuspended in PBS.

The active compound is included in the pharmaceutically acceptablecarrier in an amount sufficient to exert a therapeutically useful effectin the absence of undesirable side effects on the patient treated. Thetherapeutically effective concentration may be determined empirically bytesting the compounds in in vitro and in vivo systems described hereinand then extrapolated therefrom for dosages for humans.

The concentration of active compound in the pharmaceutical compositionwill depend on absorption, inactivation and excretion rates of theactive compound, the physicochemical characteristics of the compound,the dosage schedule, and amount administered as well as other factorsknown to those of skill in the art. For example, the amount that isdelivered is sufficient to ameliorate one or more of the symptoms ofCSF1R, FLT3, KIT, and/or PDGFRβ kinase mediated diseases.

Typically a therapeutically effective dosage should produce a serumconcentration of active ingredient of from about 1 ng/ml to about 50-100jag/ml. The pharmaceutical compositions typically should provide adosage of from about 10 mg to about 4000 mg of compound per kilogram ofbody weight per day. Pharmaceutical dosage unit forms are prepared toprovide from about 10 mg to about 1000 mg and in certain embodiments,from about 10 mg to about 500 mg, from about 20 mg to about 250 mg orfrom about 25 mg to about 100 mg of the essential active ingredient or acombination of essential ingredients per dosage unit form. In certainembodiments, the pharmaceutical dosage unit forms are prepared toprovide about 10 mg, 20 mg, 25 mg, 50 mg, 100 mg, 250 mg, 500 mg, 1000mg or 2000 mg of the essential active ingredient.

The active ingredient may be administered at once, or may be dividedinto a number of smaller doses to be administered at intervals of time.It is understood that the precise dosage and duration of treatment is afunction of the disease being treated and may be determined empiricallyusing known testing protocols or by extrapolation from in vivo or invitro test data. It is to be noted that concentrations and dosage valuesmay also vary with the severity of the condition to be alleviated. It isto be further understood that for any particular subject, specificdosage regimens should be adjusted over time according to the individualneed and the professional judgment of the person administering orsupervising the administration of the compositions, and that theconcentration ranges set forth herein are exemplary only and are notintended to limit the scope or practice of the claimed compositions.

Pharmaceutically acceptable derivatives include acids, bases, enolethers and esters, salts, esters, hydrates, solvates and prodrug forms.The derivative is selected such that its pharmacokinetic properties aresuperior to the corresponding neutral compound.

Thus, effective concentrations or amounts of one or more of thecompounds described herein or pharmaceutically acceptable derivativesthereof are mixed with a suitable pharmaceutical carrier or vehicle forsystemic, topical or local administration to form pharmaceuticalcompositions. Compounds are included in an amount effective forameliorating one or more symptoms of, or for treating or preventingCSF1R, FLT3, KIT, and/or PDGFRβ kinase mediated diseases. Theconcentration of active compound in the composition will depend onabsorption, inactivation, excretion rates of the active compound, thedosage schedule, amount administered, particular formulation as well asother factors known to those of skill in the art.

The compositions are intended to be administered by a suitable route,including, but not limited to, orally, parenterally, rectally, topicallyand locally. For oral administration, capsules and tablets can beformulated. The compositions are in liquid, semi-liquid or solid formand are formulated in a manner suitable for each route ofadministration.

Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application can include any of the following components: asterile diluent, such as water for injection, saline solution, fixedoil, polyethylene glycol, glycerine, propylene glycol, dimethylacetamide or other synthetic solvent; antimicrobial agents, such asbenzyl alcohol and methyl parabens; antioxidants, such as ascorbic acidand sodium bisulfite; chelating agents, such asethylenediaminetetraacetic acid (EDTA); buffers, such as acetates,citrates and phosphates; and agents for the adjustment of tonicity suchas sodium chloride or dextrose. Parenteral preparations can be enclosedin ampules, disposable syringes or single or multiple dose vials made ofglass, plastic or other suitable material.

In instances in which the compounds exhibit insufficient solubility,methods for solubilizing compounds may be used. Such methods are knownto those of skill in this art, and include, but are not limited to,using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants,such as TWEEN®, or dissolution in aqueous sodium bicarbonate.

Upon mixing or addition of the compound(s), the resulting mixture may bea solution, suspension, emulsion or the like. The form of the resultingmixture depends upon a number of factors, including the intended mode ofadministration and the solubility of the compound in the selectedcarrier or vehicle. In one embodiment, the effective concentration issufficient for ameliorating the symptoms of the disease, disorder orcondition treated and may be empirically determined.

The pharmaceutical compositions are provided for administration tohumans and animals in unit dosage forms, such as tablets, capsules,pills, powders, granules, sterile parenteral solutions or suspensions,and oral solutions or suspensions, and oil-water emulsions containingsuitable quantities of the compounds or pharmaceutically acceptablederivatives thereof. The pharmaceutically therapeutically activecompounds and derivatives thereof are typically formulated andadministered in unit-dosage forms or multiple-dosage forms. Unit-doseforms as used herein refer to physically discrete units suitable forhuman and animal subjects and packaged individually as is known in theart. Each unit-dose contains a predetermined quantity of thetherapeutically active compound sufficient to produce the desiredtherapeutic effect, in association with the required pharmaceuticalcarrier, vehicle or diluent. Examples of unit-dose forms include ampulesand syringes and individually packaged tablets or capsules. Unit-doseforms may be administered in fractions or multiples thereof. Amultiple-dose form is a plurality of identical unit-dosage formspackaged in a single container to be administered in segregatedunit-dose form. Examples of multiple-dose forms include vials, bottlesof tablets or capsules or bottles of pints or gallons. Hence, multipledose form is a multiple of unit-doses which are not segregated inpackaging.

Sustained-release preparations can also be prepared. Suitable examplesof sustained-release preparations include semipermeable matrices ofsolid hydrophobic polymers containing the compound provided herein,which matrices are in the form of shaped articles, e.g., films, ormicrocapsule. Examples of sustained-release matrices include polyesters,hydrogels (for example, poly(2-hydroxyethyl-methacrylate), orpoly(vinylalcohol)), polylactides, copolymers of L-glutamic acid andethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradablelactic acid-glycolic acid copolymers such as the LUPRON DEPOT™(injectable microspheres composed of lactic acid-glycolic acid copolymerand leuprolide acetate), and poly-D-(−)-3-hydroxybutyric acid. Whilepolymers such as ethylene-vinyl acetate and lactic acid-glycolic acidenable release of molecules for over 100 days, certain hydrogels releaseproteins for shorter time periods. When encapsulated compound remain inthe body for a long time, they may denature or aggregate as a result ofexposure to moisture at 37° C., resulting in a loss of biologicalactivity and possible changes in their structure. Rational strategiescan be devised for stabilization depending on the mechanism of actioninvolved. For example, if the aggregation mechanism is discovered to beintermolecular S—S bond formation through thio-disulfide interchange,stabilization may be achieved by modifying sulfhydryl residues,lyophilizing from acidic solutions, controlling moisture content, usingappropriate additives, and developing specific polymer matrixcompositions

Dosage forms or compositions containing active ingredient in the rangeof 0.005% to 100% with the balance made up from non-toxic carrier may beprepared. For oral administration, a pharmaceutically acceptablenon-toxic composition is formed by the incorporation of any of thenormally employed excipients, such as, for example pharmaceutical gradesof mannitol, lactose, starch, magnesium stearate, talcum, cellulosederivatives, sodium crosscarmellose, glucose, sucrose, magnesiumcarbonate or sodium saccharin. Such compositions include solutions,suspensions, tablets, capsules, powders and sustained releaseformulations, such as, but not limited to, implants andmicroencapsulated delivery systems, and biodegradable, biocompatiblepolymers, such as collagen, ethylene vinyl acetate, polyanhydrides,polyglycolic acid, polyorthoesters, polylactic acid and others. Methodsfor preparation of these compositions are known to those skilled in theart. The contemplated compositions may contain about 0.001%-100% activeingredient, in certain embodiments, about 0.1-85%, typically about75-95%.

The active compounds or pharmaceutically acceptable derivatives may beprepared with carriers that protect the compound against rapidelimination from the body, such as time release formulations orcoatings.

The compositions may include other active compounds to obtain desiredcombinations of properties. The compounds provided herein, orpharmaceutically acceptable derivatives thereof as described herein, mayalso be advantageously administered for therapeutic or prophylacticpurposes together with another pharmacological agent known in thegeneral art to be of value in treating one or more of the diseases ormedical conditions referred to hereinabove, such as CSF1R, FLT3, KIT,and/or PDGFRβ kinase mediated diseases. It is to be understood that suchcombination therapy constitutes a further aspect of the compositions andmethods of treatment provided herein.

1. Compositions for Oral Administration

Oral pharmaceutical dosage forms are either solid, gel or liquid. Thesolid dosage forms are tablets, capsules, granules, and bulk powders.Types of oral tablets include compressed, chewable lozenges and tabletswhich may be enteric-coated, sugar-coated or film-coated. Capsules maybe hard or soft gelatin capsules, while granules and powders may beprovided in non-effervescent or effervescent form with the combinationof other ingredients known to those skilled in the art.

In certain embodiments, the formulations are solid dosage forms, such ascapsules or tablets. The tablets, pills, capsules, troches and the likecan contain any of the following ingredients, or compounds of a similarnature: a binder; a diluent; a disintegrating agent; a lubricant; aglidant; a sweetening agent; and a flavoring agent.

Examples of binders include microcrystalline cellulose, gum tragacanth,glucose solution, acacia mucilage, gelatin solution, sucrose and starchpaste. Lubricants include talc, starch, magnesium or calcium stearate,lycopodium and stearic acid. Diluents include, for example, lactose,sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate.Glidants include, but are not limited to, colloidal silicon dioxide.Disintegrating agents include crosscarmellose sodium, sodium starchglycolate, alginic acid, corn starch, potato starch, bentonite,methylcellulose, agar and carboxymethylcellulose. Coloring agentsinclude, for example, any of the approved certified water soluble FD andC dyes, mixtures thereof; and water insoluble FD and C dyes suspended onalumina hydrate. Sweetening agents include sucrose, lactose, mannitoland artificial sweetening agents such as saccharin, and any number ofspray dried flavors. Flavoring agents include natural flavors extractedfrom plants such as fruits and synthetic blends of compounds whichproduce a pleasant sensation, such as, but not limited to peppermint andmethyl salicylate. Wetting agents include propylene glycol monostearate,sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylenelaural ether. Emetic-coatings include fatty acids, fats, waxes, shellac,ammoniated shellac and cellulose acetate phthalates. Film coatingsinclude hydroxyethylcellulose, sodium carboxymethylcellulose,polyethylene glycol 4000 and cellulose acetate phthalate.

If oral administration is desired, the compound could be provided in acomposition that protects it from the acidic environment of the stomach.For example, the composition can be formulated in an enteric coatingthat maintains its integrity in the stomach and releases the activecompound in the intestine. The composition may also be formulated incombination with an antacid or other such ingredient.

When the dosage unit form is a capsule, it can contain, in addition tomaterial of the above type, a liquid carrier such as a fatty oil. Inaddition, dosage unit forms can contain various other materials whichmodify the physical form of the dosage unit, for example, coatings ofsugar and other enteric agents. The compounds can also be administeredas a component of an elixir, suspension, syrup, wafer, sprinkle, chewinggum or the like. A syrup may contain, in addition to the activecompounds, sucrose as a sweetening agent and certain preservatives, dyesand colorings and flavors.

The active materials can also be mixed with other active materials whichdo not impair the desired action, or with materials that supplement thedesired action, such as antacids, H2 blockers, and diuretics. The activeingredient is a compound or pharmaceutically acceptable derivativethereof as described herein. Higher concentrations, up to about 98% byweight of the active ingredient may be included.

Pharmaceutically acceptable carriers included in tablets are binders,lubricants, diluents, disintegrating agents, coloring agents, flavoringagents, and wetting agents. Enteric-coated tablets, because of theenteric-coating, resist the action of stomach acid and dissolve ordisintegrate in the neutral or alkaline intestines. Sugar-coated tabletsare compressed tablets to which different layers of pharmaceuticallyacceptable substances are applied. Film-coated tablets are compressedtablets which have been coated with a polymer or other suitable coating.Multiple compressed tablets are compressed tablets made by more than onecompression cycle utilizing the pharmaceutically acceptable substancespreviously mentioned. Coloring agents may also be used in the abovedosage forms. Flavoring and sweetening agents are used in compressedtablets, sugar-coated, multiple compressed and chewable tablets.Flavoring and sweetening agents are especially useful in the formationof chewable tablets and lozenges.

Liquid oral dosage forms include aqueous solutions, emulsions,suspensions, solutions and/or suspensions reconstituted fromnon-effervescent granules and effervescent preparations reconstitutedfrom effervescent granules. Aqueous solutions include, for example,elixirs and syrups. Emulsions are either oil-in-water or water-in-oil.

Elixirs are clear, sweetened, hydroalcoholic preparations.Pharmaceutically acceptable carriers used in elixirs include solvents.Syrups are concentrated aqueous solutions of a sugar, for example,sucrose, and may contain a preservative. An emulsion is a two-phasesystem in which one liquid is dispersed in the form of small globulesthroughout another liquid. Pharmaceutically acceptable carriers used inemulsions are non-aqueous liquids, emulsifying agents and preservatives.Suspensions use pharmaceutically acceptable suspending agents andpreservatives. Pharmaceutically acceptable substances used innon-effervescent granules, to be reconstituted into a liquid oral dosageform, include diluents, sweeteners and wetting agents. Pharmaceuticallyacceptable substances used in effervescent granules, to be reconstitutedinto a liquid oral dosage form, include organic acids and a source ofcarbon dioxide. Coloring and flavoring agents are used in all of theabove dosage forms.

Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examplesof preservatives include glycerin, methyl and propylparaben, benzoicadd, sodium benzoate and alcohol. Examples of non-aqueous liquidsutilized in emulsions include mineral oil and cottonseed oil. Examplesof emulsifying agents include gelatin, acacia, tragacanth, bentonite,and surfactants such as polyoxyethylene sorbitan monooleate. Suspendingagents include sodium carboxymethylcellulose, pectin, tragacanth, Veegumand acacia. Diluents include lactose and sucrose. Sweetening agentsinclude sucrose, syrups, glycerin and artificial sweetening agents suchas saccharin. Wetting agents include propylene glycol monostearate,sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylenelauryl ether. Organic adds include citric and tartaric acid. Sources ofcarbon dioxide include sodium bicarbonate and sodium carbonate. Coloringagents include any of the approved certified water soluble FD and Cdyes, and mixtures thereof. Flavoring agents include natural flavorsextracted from plants such fruits, and synthetic blends of compoundswhich produce a pleasant taste sensation.

For a solid dosage form, the solution or suspension, in for examplepropylene carbonate, vegetable oils or triglycerides, is encapsulated ina gelatin capsule. For a liquid dosage form, the solution, e.g., forexample, in a polyethylene glycol, may be diluted with a sufficientquantity of a pharmaceutically acceptable liquid carrier, e.g., water,to be easily measured for administration.

Alternatively, liquid or semi-solid oral formulations may be prepared bydissolving or dispersing the active compound or salt in vegetable oils,glycols, triglycerides, propylene glycol esters (e.g., propylenecarbonate) and other such carriers, and encapsulating these solutions orsuspensions in hard or soft gelatin capsule shells. Other usefulformulations include, but are not limited to, those containing acompound provided herein, a dialkylated mono- or poly-alkylene glycol,including, but not limited to, 1,2-dimethoxymethane, diglyme, triglyme,tetraglyme, polyethylene glycol-350-dimethyl ether, polyethyleneglycol-550-dimethyl ether, polyethylene glycol-750-dimethyl etherwherein 350, 550 and 750 refer to the approximate average molecularweight of the polyethylene glycol, and one or more antioxidants, such asbutylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propylgallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine,lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoricacid, thiodipropionic acid and its esters, and dithiocarbamates.

Other formulations include, but are not limited to, aqueous alcoholicsolutions including a pharmaceutically acceptable acetal. Alcohols usedin these formulations are any pharmaceutically acceptable water-misciblesolvents having one or more hydroxyl groups, including, but not limitedto, propylene glycol and ethanol. Acetals include, but are not limitedto, di(lower alkyl) acetals of lower alkyl aldehydes such asacetaldehyde diethyl acetal.

In all embodiments, tablets and capsules formulations may be coated asknown by those of skill in the art in order to modify or sustaindissolution of the active ingredient. Thus, for example, they may becoated with a conventional enterically digestible coating, such asphenylsalicylate, waxes and cellulose acetate phthalate.

2. Injectables, Solutions and Emulsions

Parenteral administration, generally characterized by injection, eithersubcutaneously, intramuscularly or intravenously is also contemplatedherein. Injectables can be prepared in conventional forms, either asliquid solutions or suspensions, solid forms suitable for solution orsuspension in liquid prior to injection, or as emulsions. Suitableexcipients are, for example, water, saline, dextrose, glycerol orethanol. In addition, if desired, the pharmaceutical compositions to beadministered may also contain minor amounts of non-toxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agents,stabilizers, solubility enhancers, and other such agents, such as forexample, sodium acetate, sorbitan monolaurate, triethanolamine oleateand cyclodextrins. In one embodiment, the composition is administered asan aqueous solution with hydroxypropyl-beta-cyclodextrin (HPBCD) as anexcipient. In one embodiment, the aqueous solution contains about 1% toabout 50% HPBCD. In one embodiment, the aqueous solution contains about1%, 3%, 5%, 10% or about 20% HPBCD.

Implantation of a slow-release or sustained-release system, such that aconstant level of dosage is maintained is also contemplated herein.Briefly, a compound provided herein is dispersed in a solid innermatrix, e.g., polymethylmethacrylate, polybutylmethacrylate, plasticizedor unplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethyl eneterephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers such as hydrogels of esters of acrylicand methacrylic acid, collagen, cross-linked polyvinylalcohol andcross-linked partially hydrolyzed polyvinyl acetate, that is surroundedby an outer polymeric membrane, e.g., polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylene/vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinylchloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer, that is insoluble in body fluids.The compound diffuses through the outer polymeric membrane in a releaserate controlling step. The percentage of active compound contained insuch parenteral compositions is highly dependent on the specific naturethereof, as well as the activity of the compound and the needs of thesubject.

Parenteral administration of the compositions includes intravenous,subcutaneous and intramuscular administrations. Preparations forparenteral administration include sterile solutions ready for injection,sterile dry soluble products, such as lyophilized powders, ready to becombined with a solvent just prior to use, including hypodermic tablets,sterile suspensions ready for injection, sterile dry insoluble productsready to be combined with a vehicle just prior to use and sterileemulsions. The solutions may be either aqueous or nonaqueous.

If administered intravenously, suitable carriers include physiologicalsaline or phosphate buffered saline (PBS), and solutions containingthickening and solubilizing agents, such as glucose, polyethyleneglycol, and polypropylene glycol and mixtures thereof.

Pharmaceutically acceptable carriers used in parenteral preparationsinclude aqueous vehicles, nonaqueous vehicles, antimicrobial agents,isotonic agents, buffers, antioxidants, local anesthetics, suspendingand dispersing agents, emulsifying agents, sequestering or chelatingagents and other pharmaceutically acceptable substances.

Examples of aqueous vehicles include Sodium Chloride Injection, RingersInjection, Isotonic Dextrose Injection, Sterile Water Injection,Dextrose and Lactated Ringers Injection. Nonaqueous parenteral vehiclesinclude fixed oils of vegetable origin, cottonseed oil, corn oil, sesameoil and peanut oil. Antimicrobial agents in bacteriostatic orfungistatic concentrations must be added to parenteral preparationspackaged in multiple-dose containers which include phenols or cresols,mercurials, benzyl alcohol, chlorobutanol, methyl and propylp-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride andbenzethonium chloride. Isotonic agents include sodium chloride anddextrose. Buffers include phosphate and citrate. Antioxidants includesodium bisulfate. Local anesthetics include procaine hydrochloride.Suspending and dispersing agents include sodium carboxymethylcelluose,hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifyingagents include Polysorbate 80 (TWEEN® 80). A sequestering or chelatingagent of metal ions include EDTA. Pharmaceutical carriers also includeethyl alcohol, polyethylene glycol and propylene glycol for watermiscible vehicles and sodium hydroxide, hydrochloric acid, citric acidor lactic acid for pH adjustment.

The concentration of the pharmaceutically active compound is adjusted sothat an injection provides an effective amount to produce the desiredpharmacological effect. The exact dose depends on the age, weight andcondition of the patient or animal as is known in the art.

The unit-dose parenteral preparations are packaged in an ampule, a vialor a syringe with a needle. All preparations for parenteraladministration must be sterile, as is known and practiced in the art.

Illustratively, intravenous or intraarterial infusion of a sterileaqueous solution containing an active compound is an effective mode ofadministration. Another embodiment is a sterile aqueous or oily solutionor suspension containing an active material injected as necessary toproduce the desired pharmacological effect.

Injectables are designed for local and systemic administration.Typically a therapeutically effective dosage is formulated to contain aconcentration of at least about 0.1% w/w up to about 90% w/w or more,such as more than 1% w/w of the active compound to the treatedtissue(s). The active ingredient may be administered at once, or may bedivided into a number of smaller doses to be administered at intervalsof time. It is understood that the precise dosage and duration oftreatment is a function of the tissue being treated and may bedetermined empirically using known testing protocols or by extrapolationfrom in vivo or in vitro test data. It is to be noted thatconcentrations and dosage values may also vary with the age of theindividual treated. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of theformulations, and that the concentration ranges set forth herein areexemplary only and are not intended to limit the scope or practice ofthe claimed formulations.

The compound may be suspended in micronized or other suitable form ormay be derivatized to produce a more soluble active product or toproduce a prodrug. The form of the resulting mixture depends upon anumber of factors, including the intended mode of administration and thesolubility of the compound in the selected carrier or vehicle. Theeffective concentration is sufficient for ameliorating the symptoms ofthe condition and may be empirically determined.

3. Lyophilized Powders

Of interest herein are also lyophilized powders, which can bereconstituted for administration as solutions, emulsions and othermixtures. They may also be reconstituted and formulated as solids orgels.

The sterile, lyophilized powder is prepared by dissolving a compoundprovided herein, or a pharmaceutically acceptable derivative thereof, ina suitable solvent. The solvent may contain an excipient which improvesthe stability or other pharmacological component of the powder orreconstituted solution, prepared from the powder. Excipients that may beused include, but are not limited to, dextrose, sorbital, fructose, cornsyrup, xylitol, glycerin, glucose, sucrose,hydroxypropyl-beta-cyclodextrin (HPBCD) or other suitable agent. Thesolvent may also contain a buffer, such as citrate, sodium or potassiumphosphate or other such buffer known to those of skill in the art at,typically, about neutral pH. Subsequent sterile filtration of thesolution followed by lyophilization under standard conditions known tothose of skill in the art provides the desired formulation. Generally,the resulting solution will be apportioned into vials forlyophilization. Each vial will contain a single dosage (10-1000 mg,100-500 mg, 10-500 mg, 50-250 mg or 25-100 mg) or multiple dosages ofthe compound. The lyophilized powder can be stored under appropriateconditions, such as at about 4° C. to room temperature.

Reconstitution of this lyophilized powder with water for injectionprovides a formulation for use in parenteral administration. Forreconstitution, about 1-50 mg, about 5-35 mg, or about 9-30 mg oflyophilized powder, is added per mL of sterile water or other suitablecarrier. The precise amount depends upon the selected compound. Suchamount can be empirically determined.

4. Topical Administration

Topical mixtures are prepared as described for the local and systemicadministration. The resulting mixture may be a solution, suspension,emulsions or the like and are formulated as creams, gels, ointments,emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes,foams, aerosols, irrigations, sprays, suppositories, bandages, dermalpatches or any other formulations suitable for topical administration.

The compounds or pharmaceutically acceptable derivatives thereof may beformulated as aerosols for topical application, such as by inhalation.These formulations for administration to the respiratory tract can be inthe form of an aerosol or solution for a nebulizer, or as a microfinepowder for insufflation, alone or in combination with an inert carriersuch as lactose. In such a case, the particles of the formulation willtypically have diameters of less than 50 microns or less than 10microns.

The compounds may be formulated for local or topical application, suchas for topical application to the skin and mucous membranes, such as inthe eye, in the form of gels, creams, and lotions and for application tothe eye or for intracisternal or intraspinal application. Topicaladministration is contemplated for transdermal delivery and also foradministration to the eyes or mucosa, or for inhalation therapies. Nasalsolutions of the active compound alone or in combination with otherpharmaceutically acceptable excipients can also be administered.

These solutions, particularly those intended for ophthalmic use, may beformulated as 0.01%-10% isotonic solutions, pH about 5-7, withappropriate salts.

5. Compositions for Other Routes of Administration

Other routes of administration, such as topical application, transdermalpatches, and rectal administration are also contemplated herein.

For example, pharmaceutical dosage forms for rectal administration arerectal suppositories, capsules and tablets for systemic effect. Rectalsuppositories are used herein mean solid bodies for insertion into therectum which melt or soften at body temperature releasing one or morepharmacologically or therapeutically active ingredients.Pharmaceutically acceptable substances utilized in rectal suppositoriesare bases or vehicles and agents to raise the melting point. Examples ofbases include cocoa butter (theobroma oil), glycerin-gelatin, carbowax(polyoxyethylene glycol) and appropriate mixtures of mono-, di- andtriglycerides of fatty acids. Combinations of the various bases may beused. Agents to raise the melting point of suppositories includespermaceti and wax. Rectal suppositories may be prepared either by thecompressed method or by molding. The typical weight of a rectalsuppository is about 2 to 3 gm.

Tablets and capsules for rectal administration are manufactured usingthe same pharmaceutically acceptable substance and by the same methodsas for formulations for oral administration.

6. Sustained Release Compositions

Active ingredients provided herein can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; and U.S. Pat. Nos. 4,008,719, 5,674,533, 5,059,595,5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, 5,639,480,5,733,566, 5,739,108, 5,891,474, 5,922,356, 5,972,891, 5,980,945,5,993,855, 6,045,830, 6,087,324, 6,113,943, 6,197,350, 6,248,363,6,264,970, 6,267,981, 6,376,461, 6,419,961, 6,589,548, 6,613,358,6,699,500 and 6,740,634, each of which is incorporated herein byreference. Such dosage forms can be used to provide slow orcontrolled-release of one or more active ingredients using, for example,hydropropylmethyl cellulose, other polymer matrices, gels, permeablemembranes, osmotic systems, multilayer coatings, microparticles,liposomes, microspheres, or a combination thereof to provide the desiredrelease profile in varying proportions. Suitable controlled-releaseformulations known to those of ordinary skill in the art, includingthose described herein, can be readily selected for use with the activeingredients provided herein.

All controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. Advantages of controlled-releaseformulations include extended activity of the drug, reduced dosagefrequency, and increased patient compliance. In addition,controlled-release formulations can be used to affect the time of onsetof action or other characteristics, such as blood levels of the drug,and can thus affect the occurrence of side (e.g., adverse) effects.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled-release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

In certain embodiments, the agent may be administered using intravenousinfusion, an implantable osmotic pump, a transdermal patch, liposomes,or other modes of administration. In one embodiment, a pump may be used.In another embodiment, polymeric materials can be used. In yet anotherembodiment, a controlled release system can be placed in proximity ofthe therapeutic target, i.e., thus requiring only a fraction of thesystemic dose. In some embodiments, a controlled release device isintroduced into a subject in proximity of the site of inappropriateimmune activation or a tumor. The active ingredient can be dispersed ina solid inner matrix, e.g., polymethylmethacrylate,polybutylmethacrylate, plasticized or unplasticized polyvinylchloride,plasticized nylon, plasticized polyethyleneterephthalate, naturalrubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene,ethylene-vinylacetate copolymers, silicone rubbers,polydimethylsiloxanes, silicone carbonate copolymers, hydrophilicpolymers such as hydrogels of esters of acrylic and methacrylic acid,collagen, cross-linked polyvinylalcohol and cross-linked partiallyhydrolyzed polyvinyl acetate, that is surrounded by an outer polymericmembrane, e.g., polyethylene, polypropylene, ethylene/propylenecopolymers, ethylene/ethyl acrylate copolymers, ethylene/vinylacetatecopolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber,chlorinated polyethylene, polyvinylchloride, vinylchloride copolymerswith vinyl acetate, vinylidene chloride, ethylene and propylene, ionomerpolyethylene terephthalate, butyl rubber epichlorohydrin rubbers,ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcoholterpolymer, and ethylene/vinyloxyethanol copolymer, that is insoluble inbody fluids. The active ingredient then diffuses through the outerpolymeric membrane in a release rate controlling step. The percentage ofactive ingredient contained in such parenteral compositions is highlydependent on the specific nature thereof, as well as the needs of thesubject.

7. Targeted Formulations

The compounds provided herein, or pharmaceutically acceptablederivatives thereof, may also be formulated to be targeted to aparticular tissue, receptor, or other area of the body of the subject tobe treated. Many such targeting methods are well known to those of skillin the art. All such targeting methods are contemplated herein for usein the instant compositions. For non-limiting examples of targetingmethods, see, e.g., U.S. Pat. Nos. 6,316,652, 6,274,552, 6,271,359,6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060,082,6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252,5,840,674, 5,759,542 and 5,709,874.

In one embodiment, liposomal suspensions, including tissue-targetedliposomes, such as tumor-targeted liposomes, may also be suitable aspharmaceutically acceptable carriers. These may be prepared according tomethods known to those skilled in the art. Briefly, liposomes such asmultilamellar vesicles (MLV's) may be formed by drying down eggphosphatidyl choline and brain phosphatidyl serine (7:3 molar ratio) onthe inside of a flask. A solution of a compound provided herein inphosphate buffered saline lacking divalent cations (PBS) is added andthe flask shaken until the lipid film is dispersed. The resultingvesicles are washed to remove unencapsulated compound, pelleted bycentrifugation, and then resuspended in PBS.

D. EVALUATION OF THE ACTIVITY OF THE COMPOUNDS

Standard physiological, pharmacological and biochemical procedures areavailable for testing the compounds to identify those that possessbiological activities that modulate the activity of CSF1R, FLT3, KIT,and/or PDGFRβ kinase.

Such assays include, for example, biochemical assays such as bindingassays, radioactivity incorporation assays, as well as a variety of cellbased assays.

In certain embodiments, the compounds disclosed herein are tested in anM-NFS-60 cell proliferation assay to determine their cellular potencyagainst CSF1R. M-NFS-60s are mouse monocytic cells that depend on thebinding of the ligand M-CSF to its receptor, CSF1R, to proliferate.Inhibition of CSF1R kinase activity will cause reduced growth and/orcell death. This assay assesses the potency of compounds as CSF1Rinhibitors by measuring the reduction of Alamar Blue reagent by viablecells. An exemplary assay is described in the Examples section.

In certain embodiments, competition binding assays were performed asdescribed in Fabian et al., Nature Biotechnology 2005, 23, 329-336.

In one embodiment, the compounds provided herein were found to have Kdsof about or less than about 150 nM against FLT3 kinase. In oneembodiment, the compounds provided herein have Kds of about 1 nM orless, 3 nM or less, 5 nM or less, 0.1-2 nM, 2-5 nM, 5-10 nM, 10-25 nM,25-50 nM, or 50-150 nM, against FLT3 kinase. In one embodiment, thecompounds provided herein have Kds of less than about 50, 25, 10, 5, 4,3, 2, or 1 nM against FLT3 kinase. In another embodiment, the compoundsprovided herein have Kds of about or less than about 5 nM, 3 nM or 1 nMagainst FLT3 kinase.

In one embodiment, the compounds provided herein were found to have Kdsof about or less than about 50 nM against KIT kinase. In one embodiment,the compounds provided herein have Kds of about 1 nM or less, 3 nM orless, 0.1-2 nM, 2-5 nM, 5-10 nM, or 10-25 M, against KIT kinase. In oneembodiment, the compounds provided herein have Kds of less than about10, 5, 4, 3, 2 or 1 nM against KIT kinase. In another embodiment, thecompounds provided herein have Kds of about or less than about 5 nM, 3nM or 1 nM against KIT kinase.

In one embodiment, the compounds provided herein were found to have Kdsof about or less than about 100 nM or 50 nM against PDGFRβ kinase. Inone embodiment, the compounds provided herein have Kds of about about 1nM or less, 3 nM or less, 0.1-2 nM, 2-5 nM, 5-10 nM, or 10-25 M, againstPDGFRβ kinase. In one embodiment, the compounds provided herein have Kdsof less than about 10, 5, 4, 3, 2 or 1 nM against PDGFRβ kinase. Inanother embodiment, the compounds provided herein have Kds of about orless than about 5 nM, 3 nM or 1 nM against PDGFRβ kinase.

In one embodiment, the compounds provided herein were found to have Kdsof about or less than about 1 CtM against CSF1R kinase. In oneembodiment, the compounds provided herein were found to have Kds of lessthan about 1, 0.5, 0.1 or 0.01 μM against CSF1R kinase. In oneembodiment, the compounds provided herein were found to have Kds of lessthan about 300, 200, 100, 50, 10, 5, 4, 3, 2, or 1 nM against CSF1Rkinase. In another embodiment, the compounds provided herein were foundto have Kds of about or less than about 5 nM, 3 nM or 1 nM against CSF1Rkinase.

E. METHODS OF USE OF THE COMPOUNDS AND COMPOSITIONS

Also provided herein are methods of using the disclosed compounds andcompositions, or pharmaceutically acceptable salts, solvates, hydrates,clathrates, single stereoisomers, mixture of stereoisomers, racemicmixture of stereoisomers or prodrugs thereof, for the treatment,prevention, or amelioration of a disease or disorder that is mediated orotherwise affected via protein kinase activiy or one or more symptoms ofdiseases or disorders that are mediated or otherwise affected viaprotein kinase activity (see, Krause and Van Etten, N Engl J Med (2005)353(2):172-187, Blume-Jensen and Hunter, Nature (2001) 411(17): 355-365and Plowman et al., DN&P, 7:334-339 (1994)).

In certain embodiments, provided herein are methods of treating thefollowing diseases or disorders:

1) carcinomas include Kit-mediated and/or CSF1R-mediated carcinomas,adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma,teratocarcinoma, head and neck cancer, brain cancer, intracranialcarcinoma, glioblastoma including PDGFR-mediated glioblastoma,glioblastoma multiforme including PDGFR-mediated glioblastomamultiforme, neuroblastoma, cancer of the larynx, multiple endocrineneoplasias 2A and 2B (MENS 2A and MENS 2B) including RET-mediated MENS,thyroid cancer, including sporadic and familial medullary thyroidcarcinoma, papillary thyroid carcinoma, parathyroid carcinoma includingany RET-mediated thyroid carcinoma, follicular thyroid cancer,anaplastic thyroid cancer, bronchial carcinoid, oat cell carcinoma, lungcancer, small-cell lung cancer including flt-3 and/or Kit-mediated smallcell lung cancer, stomach/gastric cancer, gastrointestinal cancer,gastrointestinal stromal tumors (GIST) including Kit-mediated GIST andPDGFRα-mediated GIST, colon cancer, colorectal cancer, pancreaticcancer, islet cell carcinoma, hepatic/liver cancer, metastases to theliver, bladder cancer, renal cell cancer including PDGFR-mediated renalcell cancer, cancers of the genitourinary tract, ovarian cancerincluding Kit-mediated and/or PDGFR-mediated and/or CSF1R-mediatedovarian cancer, endometrial cancer including CSF1R-mediated endometrialcancer, cervical cancer, breast cancer including Flt-3-mediated and/orPDGFR-mediated and/or CSF1R-mediated breast cancer, prostate cancerincluding Kit-mediated prostate cancer, germ cell tumors includingKit-mediated germ cell tumors, seminomas including Kit-mediatedseminomas, dysgerminomas, including Kit-mediated dysgerminomas, melanomaincluding PDGFR-mediated melanoma, metastases to the bone includingCSF1R-mediated bone metastases, metastatic tumors includingVEGFR-mediated and/or CSF1R metastatic tumors, stromal tumors,neuroendocrine tumors, tumor angiogenesis including VEGFR-mediatedand/or CSF1R-mediated tumor angiogenesis, mixed mesodermal tumors;

2) sarcomas including PDGFR-mediated sarcomas, osteosarcoma, osteogenicsarcoma, bone cancer, glioma including PDGFR-mediated and/orCSF1R-mediated glioma, astrocytoma, vascular tumors includingVEGFR-mediated vascular tumors, Kaposi's sarcoma, carcinosarcoma,hemangiosarcomas including VEGFR3-mediated hemangiosarcomas,lymphangiosarcoma including VEGFR3-mediated lymphangiosarcoma;

3) liquid tumors, myeloma, multiple myeloma, leukemia,myeloproliferative diseases (MPD), acute myeloid leukemia (AML)including flt-3 mediated and/or KIT-mediated and/or CSF1R-mediated acutemyeloid leukemia, chronic myeloid leukemias (CML) includingFlt-3-mediated and/or PDGFR-mediated chronic myeloid leukemia,myelodysplastic leukemias including Flt-3-mediated myelodysplasticleukemia, acute megakaryoblastic leukemia CSF1R-mediated acutemegakaryoblastic leukemia, myelodysplastic syndrome, including Flt-3mediated and/or Kit-mediated myelodysplastic syndrome (MDS), idiopathichypereosinophilic syndrome (HES) including PDGFR-mediated HES, chroniceosinophilic leukemia (CEL) including PDGFR-mediated CEL, chronicmyelomonocytic leukemia (CMML), mast cell leukemia includingKit-mediated mast cell leukemia, or systemic mastocytosis includingKit-mediated systemic mastocytosis; and

4) lymphoma, Hodgkin's lymphoma, lymphoproliferative diseases, acutelymphoblastic leukemia (ALL), B-cell acute lymphoblastic leukemias,T-cell acute lymphoblastic leukemias, natural killer (NK) cell leukemia,B-cell lymphoma, T-cell lymphoma, and natural killer (NK) cell lymphoma,any of which may be Flt-3 mediated and/or PDGFR-mediated, Langerhanscell histiocytosis including CSF1R-mediated and flt-3-mediatedLangerhans cell histiocytosis, mast cell tumors and mastocytosis;

2) Nonmalignant proliferation diseases; atherosclerosis includingCSF1R-mediated atherosclerosis or PDGFR-mediated atherosclerosis,restenosis following vascular angioplasty including PDGFR-mediatedrestenosis, and fibroproliferative disorders such as obliterativebronchiolitis and idiopathic myelofibrosis, both of which may bePDGFR-mediated, pulmonary fibrosis and also obesity and obesity-inducedinsulin resistance, either of which may be CSF1R mediated;

5) Inflammatory diseases or immune disorders including autoimmunediseases, which include, but is not limited to, tissue transplantrejection, graft-versus-host disease, wound healing, kidney disease,multiple sclerosis, thyroiditis, type 1 diabetes, sarcoidosis, allergicrhinitis, nephritis, Alzheimer's disease, inflammatory bowel diseaseincluding Crohn's disease and ulcerative colitis (UC), systemic lupuserythematosis (SLE), cutaneous lupus erythematosis (SLE), lupusnephritis, glomerular nephritis, arthritis, osteoarthritis, rheumatoidarthritis, psoriatic arthritis, inflammatory arthritis, osteoporosis,asthma and chronic obstructive pulmonary disease (COPD), allergicasthma, ankylosing spondylitis, including any of the aforementioneddiseases which are flt-3-mediated and/or CSF1R-mediated and/orKIT-mediated;

6) Bone diseases including disorders relating to the mineralization,formation and resorption of the bone, including but not limited toosteoporosis, glucocorticoid-induced osteoporosis, periodontitis, boneloss due to cancer therapy, periprosthetic osteolysis, Paget's disease,hypercalcemia, hypercalcemia of malignancy, osteomyelitis, and bonepain; and

7) Infectious diseases mediated either via viral or bacterial pathogensand sepsis, including KIT-mediated and/or CSF1R-mediated sepsis.

Also provided are methods of modulating the activity, or subcellulardistribution, of kinases in a cell, tissue or whole organism, using thecompounds and compositions provided herein, or pharmaceuticallyacceptable derivatives thereof. In one embodiment, provided herein aremethods of modulating the activity of FLT3 activity in a cell, tissue orwhole organism using the compounds and compositions provided herein, orpharmaceutically acceptable derivatives thereof. In one embodiment,provided herein are methods of modulating the activity of CSF1R activityin a cell, tissue or whole organism using the compounds and compositionsprovided herein, or pharmaceutically acceptable derivatives thereof. Inone embodiment, provided herein are methods of modulating the activityof KIT activity in a cell, tissue or whole organism using the compoundsand compositions provided herein, or pharmaceutically acceptablederivatives thereof.

In one embodiment, the methods provided herein are for treatingtumor-associated osteolysis, osteoporosis including ovariectomy-inducedbone loss, orthopedic implant failure, renal inflammation andglomerulonephritis, transplant rejection including renal and bone marrowallografts and skin xenograft, obesity, Alzheimer's Disease andLangerhans cell histiocytosis. In one embodiment, the methods providedherein are for treating chronic skin disorders including psoriasis.

In another embodiment, a method for treating periodontitis, Langerhanscell histiocytosis, osteoporosis, Paget's disease of bone (PDB), boneloss due to cancer therapy, periprosthetic osteolysis,glucocorticoid-induced osteoporosis, rheumatoid arthritis, psoriaticarthritis, osteoarthritis, and/or inflammatory arthritis is providedherein.

In one embodiment, the methods provided herein are for treating bonediseases including disorders relating to the mineralization, formationand resorption of the bone, including but not limited to osteoporosis,Paget's disease, hypercalcemia, hypercalcemia of malignancy, osteolysis,osteomyelitis, and bone pain.

In one embodiment, the methods provided herein are for treating cancers,including, but not limited to liquid tumors, head and neck cancer,(originating in lip, oral cavity, oropharynx, hypopharynx, larynx,nasopharynx, nasal cavity and paranasal sinuses or salivary glands);lung cancer, including small cell lung cancer, non-small cell lungcancer; gastrointestinal tract cancers, including esophageal cancer,gastric cancer, colorectal cancer, anal cancer, pancreatic cancer, livercancer, gallbladder cancer, extrahepatic bile duct cancer, cancer of theampulla of vater; breast cancer; gynecologic cancers, including, cancerof uterine cervix, cancer of the uterine body, vaginal cancer, vulvarcancer, ovarian cancer, gestational trophoblastic cancer neoplasia;testicular cancer; urinary tract cancers, including, renal cancer,urinary bladder cancer, prostate cancer, penile cancer, urethral cancer;neurologic tumors; tenosynovial giant cell tumors, endocrine neoplasms,including carcinoid and islet cell tumors, pheochromocytoma, adrenalcortical carcinoma, parathyroid carcinoma and metastases to endocrineglands. In another embodiment, the methods provided herein are fortreating carcinoma, breast cancer, ovarian cancer, bone metastases,osteoporosis, Paget's disease, hypercalcemia, hypercalcemia ofmalignancy, osteolysis, osteomyelitis, bone pain, inflammatory boweldisease (IBD), Crohn's disease, ulcerative colitis (UC), systemic lupuserythematosis (SLE), lupus nephritis, glomerular nephritis, arthritis,osteoarthritis, rheumatoid arthritis, osteoporosis, asthma, allergicasthma, chronic obstructive pulmonary disease (COPD), psoriasis,ankylosing spondylitis, and multiple sclerosis. In another embodiment,provided herein are methods for treating inflammatory diseases of theeye including conjunctivitis, uveitis, iritis, scleritis, blepheritis,meibomitis and optical neuritis. In yet another embodiment, providedherein are methods for treating glaucoma, diabetic retinopathy andmacular degeneration.

Further examples of cancers are basal cell carcinoma; squamous cellcarcinoma; chondrosarcoma (a cancer arising in cartilage cells);mesenchymal-chondrosarcoma; soft tissue sarcomas, including, malignanttumours that may arise in any of the mesodermal tissues (muscles,tendons, vessels that carry blood or lymph, joints and fat); soft tissuesarcomas include; alveolar soft-part sarcoma, angiosarcoma,fibrosarcoma, leiomyosarcoma, liposarcoma, malignant fibroushistiocytoma, hemangiopericytoma, mesenchymoma, schwannoma, peripheralneuroectodermal tumours, rhabdomyosarcoma, synovial sarcoma; gestationaltrophoblastic tumour (malignancy in which the tissues formed in theuterus following conception become cancerous); Hodgkin's lymphoma andlaryngeal cancer.

In one embodiment, the cancer is a leukemia. In one embodiment, theleukemia is chronic lymphocytic leukemia, chronic myelocytic leukemia,acute lymphoblastic leukemia, acute myeloid leukemia, and acutemyeloblastic leukemia.

In another embodiment, the leukemia is acute leukemia. In oneembodiment, the acute leukemia is acute myeloid leukemia (AML). In oneembodiment, acute myeloid leukemia is undifferentiated AML (M0),myeloblastic leukemia (M1), myeloblastic leukemia (M2), promyelocyticleukemia (M3 or M3 variant [M3V]), myelomonocytic leukemia (M4 or M4variant with eosinophilia [M4E]), monocytic leukemia (M5),erythroleukemia (M6), or megakaryoblastic leukemia (M7). In anotherembodiment, the acute myeloid leukemia is undifferentiated AML (M0). Inyet another embodiment, the acute myeloid leukemia is myeloblasticleukemia (M1). In yet another embodiment, the acute myeloid leukemia ismyeloblastic leukemia (M2). In yet another embodiment, the acute myeloidleukemia is promyelocytic leukemia (M3 or M3 variant [M3V]). In yetanother embodiment, the acute myeloid leukemia is myelomonocyticleukemia (M4 or M4 variant with eosinophilia [M4E]). In yet anotherembodiment, the acute myeloid leukemia is monocytic leukemia (M5). Inyet another embodiment, the acute myeloid leukemia is erythroleukemia(M6). In yet another embodiment, the acute myeloid leukemia ismegakaryoblastic leukemia (M7). In yet another embodiment, the acutemyeloid leukemia is promyelocytic leukemia

In another embodiment, the acute leukemia is acute lymphocytic leukemia(ALL). In one embodiment, the acute lymphocytic leukemia is leukemiathat originates in the blast cells of the bone marrow (B-cells), thymus(T-cells), or lymph nodes. The acute lymphocytic leukemia is categorizedaccording to the French-American-British (FAB) MorphologicalClassification Scheme as L1—Mature-appearing lymphoblasts (T-cells orpre-B-cells), L2—Immature and pleomorphic (variously shaped)lymphoblasts (T-cells or pre-B-cells), and L3—Lymphoblasts (B-cells;Burkitt's cells). In another embodiment, the acute lymphocytic leukemiaoriginates in the blast cells of the bone marrow (B-cells). In yetanother embodiment, the acute lymphocytic leukemia originates in thethymus (T-cells). In yet another embodiment, the acute lymphocyticleukemia originates in the lymph nodes. In yet another embodiment, theacute lymphocytic leukemia is L1 type characterized by mature-appearinglymphoblasts (T-cells or pre-B-cells). In yet another embodiment, theacute lymphocytic leukemia is L2 type characterized by immature andpleomorphic (variously shaped) lymphoblasts (T-cells or pre-B-cells). Inyet another embodiment, the acute lymphocytic leukemia is L3 typecharacterized by lymphoblasts (B-cells; Burkitt's cells).

In yet another embodiment, the leukemia is T-cell leukemia. In oneembodiment, the T-cell leukemia is peripheral T-cell leukemia, T-celllymphoblastic leukemia, cutaneous T-cell leukemia, and adult T-cellleukemia. In another embodiment, the T-cell leukemia is peripheralT-cell leukemia. In yet another embodiment, the T-cell leukemia isT-cell lymphoblastic leukemia. In yet another embodiment, the T-cellleukemia is cutaneous T-cell leukemia. In still another embodiment, theT-cell leukemia is adult T-cell leukemia.

In yet another embodiment, the leukemia is Philadelphia positive. In oneembodiment, the Philadelphia positive leukemia is Philadelphia positiveAML, including, but not limited to, undifferentiated AML (M0),myeloblastic leukemia (M1), myeloblastic leukemia (M2), promyelocyticleukemia (M3 or M3 variant [M3V]), myelomonocytic leukemia (M4 or M4variant with eosinophilia [M4E]), monocytic leukemia (M5),erythroleukemia (M6), or megakaryoblastic leukemia (M7). In anotherembodiment, the Philadelphia positive leukemia is Philadelphia positiveALL.

In still another embodiment, the leukemia is drug resistant. In stillanother embodiment, the gastrointestinal stromal tumor (GIST) is drugresistant. In still another embodiment, the melanoma is drug resistant.In one embodiment, the subject has developed drug resistance to theanticancer therapy.

The cancers to be treated herein may be primary or metastatic. In oneembodiment, the cancer is a solid or blood born metastatic tumor. Inanother embodiment, the cancer is metastatic cancer of bone.

Also provided are methods of modulating the activity, or subcellulardistribution, of CSF1R kinase in a cell, tissue or whole organism, usingthe compounds and compositions provided herein, or pharmaceuticallyacceptable salts, solvates, hydrates, clathrates, single stereoisomers,mixture of stereoisomers or racemic mixture of stereoisomers thereof.

The active ingredient(s) in one embodiment are administered in an amountsufficient to deliver to a patient a therapeutically effective amount ofthe active compound in order to e.g., treat the diseases describedherein, without causing serious toxic effects in a treated subject.

A typical dose of the compound may be in the range of from about 1 toabout 50 mg/kg, from about 1 to about 20 mg/kg, from about 0.1 to about10 mg/kg, from about 0.5 mg/kg to about 10 mg/kg, of body weight perday, more generally from about 0.1 to about 100 mg/kg body weight of therecipient per day. Alternatively, a typical dose of the compound may bein the range of from about 50 mg to about 500 mg. Lower dosages may beused, for example, doses of about 0.5-100 mg, 0.5-10 mg, or 0.5-5 mg perkilogram body weight per day. Even lower doses may be useful, and thusranges can include from about 0.1-0.5 mg/kg body weight of the recipientper day. The effective dosage range of the pharmaceutically acceptablederivatives is calculated based on the weight of the parent compound tobe delivered. If the derivative compound itself exhibits activity, thenthe effective dosage can be estimated as above using the weight of thederivative, or by other means known to those of skill in the art.

The compounds are conveniently administered in units of any suitabledosage form, including but not limited to one containing from about 1 to2000 mg, from about 10 to 1000 mg, or from about 25 to 700 mg of activeingredient per unit dosage form. In one embodiment, the unit dose isselected from 12, 18, 25, 27, 40, 50, 60, 90, 100, 135, 200, 250, 300,400, 450, 500, 600, 675, 700, 800, 900 and 1000 mgs. For example, anoral dosage of from about 25 to 1000 mg is usually convenient, includingin one or multiple dosage forms of 10, 12, 18, 25, 27, 40, 50, 60, 90,100, 135, 200, 250, 300, 400, 450, 500, 600, 675, 700, 800, 900 or 1000mgs. In certain embodiments, lower dosages may be used, for example,from about 10-100 or 1-50 mgs. Also contemplated are doses of 0.1-50 mg,0.1-20 mg, or 0.1-10 mg. Furthermore, lower doses may be utilized in thecase of administration by a non-oral route, as for example, by injectionor inhalation.

The active ingredient may be administered at once, or may be dividedinto a number of smaller doses to be administered at intervals of time.It is understood that the precise dosage and duration of treatment is afunction of the disease being treated and may be determined empiricallyusing known testing protocols or by extrapolation from in vivo or invitro test data. It is to be noted that concentrations and dosage valuesmay also vary with the severity of the condition to be alleviated. It isto be further understood that for any particular subject, specificdosage regimens should be adjusted over time according to the individualneed and the professional judgment of the person administering orsupervising the administration of the compositions, and that theconcentration ranges set forth herein are exemplary only and are notintended to limit the scope or practice of the compositions providedherein.

In certain embodiments, the compound or composition provided herein canbe administered as a single once-a-day dose (QD) or as divided dosesthroughout a day. In particular embodiments, the compound or compositionis administered four times per day (QID). In particular embodiments, thecompound or composition is administered three times per day (TID). Inparticular embodiments, the compound or composition is administered twotimes per day (BID). In particular embodiments, the compound orcomposition is administered once per day (QD).

The administration can also be continuous (i.e., daily for consecutivedays or every day) or intermittent. The term “intermittent” or“intermittently” as used herein is intended to mean stopping andstarting at either regular or irregular intervals. For example,intermittent administration of the compound of Formula I may beadministration for one to six days per week or administration onalternate days.

In one embodiment, the compound or composition provided herein isadministered intermittently. In yet another embodiment, the compound orcomposition provided herein is administered intermittently once weekly,twice weekly or three times weekly. In yet another embodiment, thecompound or composition provided herein is administered once weekly. Inyet another embodiment, the compound or composition provided herein isadministered twice weekly. In yet another embodiment, the compound orcomposition provided herein is administered three times weekly. In oneembodiment, the compound or composition provided herein is administeredQD intermittently once weekly, twice weekly or three times weekly. Inyet another embodiment, the compound or composition provided herein isadministered QD once weekly. In another embodiment, the compound orcomposition provided herein is administered QD twice weekly. In anotherembodiment, the compound or composition provided herein is administeredQD three times weekly.

In one embodiment, the active ingredient is administered to achieve peakplasma concentrations of the active compound of from about 0.02 to 20μM, from about 0.2 to about 5 μM or from about 0.5 to 10 μM. Forexample, this can be achieved by intravenous injection of a 0.1 to 5%solution of active ingredient, optionally in saline, or administered asa bolus of active ingredient. It is to be understood that for anyparticular subject, specific dosage regimens should be adjusted overtime to meet individual needs, and will vary depending upon absorption,inactivation and excretion rates of the drug. The concentrations setforth here are exemplary only and are not intended to limit the scope orpractice of the claimed composition. The active ingredient may beadministered all at once, or may be divided into a number of smallerdoses to be administered at varying intervals of time.

The subject matter has been described in an illustrative manner, and itis to be understood that the terminology used is intended to be in thenature of description rather than of limitation. Thus, it will beappreciated by those of skill in the art that conditions such as choiceof solvent, temperature of reaction, volumes, reaction time may varywhile still producing the desired compounds. In addition, one of skillin the art will also appreciate that many of the reagents provided inthe examples may be substituted with other suitable reagents. See, e.g.,Smith & March, Advanced Organic Chemistry, 5^(th) ed. (2001).

F. COMBINATION THERAPY

Furthermore, it will be understood by those skilled in the art that thecompounds, isomers, and pharmaceutically acceptable salts, hydrates,solvates provided herein, including pharmaceutical compositions andformulations containing these compounds, can be used in a wide varietyof combination therapies to treat the conditions and diseases describedabove. Thus, also contemplated herein is the use of compounds, andpharmaceutically acceptable salts provided herein in combination withother active pharmaceutical agents for the treatment of thedisease/conditions described herein.

In one embodiment, such additional pharmaceutical agents include withoutlimitation anti-cancer agents (including chemotherapeutic agents andanti-proliferative agents), anti-inflammatory agents, immunomodulatoryagents or immunosuppressive agents.

In certain embodiments, the anti-cancer agents include anti-metabolites(e.g., 5-fluoro-uracil, cytarabine, clofarabine, methotrexate,fludarabine and others), antimicrotubule agents (e.g., vinca alkaloidssuch as vincristine, vinblastine; taxanes such as paclitaxel anddocetaxel), alkylating agents (e.g., cyclophosphamide, melphalan,carmustine, nitrosoureas such as bischloroethylnitrosurea andhydroxyurea), platinum agents (e.g. cisplatin, carboplatin, oxaliplatin,satraplatin and CI-973), anthracyclines (e.g., doxrubicin anddaunorubicin), antitumor antibiotics (e.g., mitomycin, idarubicin,adriamycin and daunomycin), topoisomerase inhibitors (e.g., etoposideand camptothecins), anti-angiogenesis agents (e.g. Sutent®, sorafeniband Bevacizumab) or any other cytotoxic agents, (e.g. estramustinephosphate, prednimustine), hormones or hormone agonists, antagonists,partial agonists or partial antagonists, kinase inhibitors (such asimatinib), and radiation treatment.

In certain embodiments, the anti-inflammatory agents include matrixmetalloproteinase inhibitors, inhibitors of pro-inflammatory cytokines(e.g., anti-TNF molecules, TNF soluble receptors, and IL1) non-steroidalanti-inflammatory drugs (NSAIDs) such as prostaglandin synthaseinhibitors (e.g., choline magnesium salicylate and salicylsalicyclicacid), COX-1 or COX-2 inhibitors, glucocorticoid receptor agonists(e.g., corticosteroids, methylprednisone, prednisone, and cortisone) orantifolates such as methotrexate.

The compound or composition provided herein, or pharmaceuticallyacceptable salt of the compound, may be administered simultaneouslywith, prior to, or after administration of one or more of the aboveagents.

Pharmaceutical compositions containing a compound provided herein orpharmaceutically acceptable salt thereof, and one or more of the aboveagents are also provided.

Also provided, in one embodiment, is a combination therapy that treatsor prevents the onset of the symptoms, or associated complications ofcancer and related diseases and disorders, said therapy comprising theadministration to a subject in need thereof, one of the compounds orcompositions disclosed herein, or pharmaceutically acceptable saltsthereof, with one or more anti-cancer agents. Also provided, in anotherembodiment, is a combination therapy that treats or prevents the onsetof the symptom of osteoporosis and related diseases and disorders, saidtherapy comprising the administration to a subject in need thereof, oneof the compounds or compositions disclosed herein, or pharmaceuticallyacceptable salts thereof, with one or more anti-inflammatory orimmunomodulatory agents. Also provided, in yet another embodiment, is acombination therapy that treats or prevents the onset of the symptom ofrheumatoid arthritis and related diseases and disorders, said therapycomprising the administration to a subject in need thereof, one of thecompounds or compositions disclosed herein, or pharmaceuticallyacceptable salts thereof, with one or more anti-inflammatory orimmunomodulatory agents.

G. PREPARATION OF COMPOUNDS

Starting materials in the synthesis examples provided herein are eitheravailable from commercial sources or via literature procedures (e.g.,March Advanced Organic Chemistry: Reactions, Mechanisms, and Structure,(1992) 4th Ed.; Wiley Interscience, New York). All commerciallyavailable compounds were used without further purification unlessotherwise indicated. 300 MHz Proton (¹H) nuclear magnetic resonance(NMR) spectra were recorded on a Bruker Avance 300 NMR spectrometer.Significant peaks are tabulated and typically include: number ofprotons, and multiplicity (s, singlet; d, double; t, triplet; q,quartet; m, multiplet; br s, broad singlet). Chemical shifts arereported as parts per million (6) relative to tetramethylsilane. Lowresolution mass spectra (MS) were obtained as electrospray ionization(ESI) mass spectra, which were recorded on a Shimadzu HPLC/MS instrumentusing reverse-phase conditions (acetonitrile/water, 0.05% acetic acid).Preparative reverse phase HPLC was typically performed using a VarianHPLC system equipped with a Phenomenex phenylhexyl, a Phenomenex LunaC18, or a Varian Pursuit diphenyl reverse phase column; typical elutionconditions utilized a gradient containing an increasing composition oforganic cosolvent (0.05% HOAc/CH₃CN or 0.05% HOAc/MeOH) to aqueouscosolvent (0.05% aq HOAc). Silica gel chromatography was eitherperformed manually, typically following the published procedure forflash chromatography (Still et al. (1978) J. Org. Chem. 43:2923), or onan automated system (for example, Biotage SP instrument) usingpre-packed silica gel columns.

It is understood that in the following description, combinations ofsubstituents and/or variables of the depicted formulae are permissibleonly if such contributions result in stable compounds under standardconditions.

It will also be appreciated by those skilled in the art that in theprocess described below, the functional groups of intermediate compoundsmay need to be protected by suitable protecting groups. Such functionalgroups include hydroxy, amino, mercapto and carboxylic acid. Suitableprotecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl(e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl),tetrahydropyranyl, benzyl, and the like. Suitable protecting groups foramino, amidino and guanidino include t-butoxycarbonyl,benzyloxycarbonyl, and the like. Suitable protecting groups for mercaptoinclude —C(O)—R (where R is alkyl, aryl or aralkyl), p-methoxybenzyl,trityl and the like. Suitable protecting groups for carboxylic acidinclude alkyl, aryl or aralkyl esters.

Protecting groups may be added or removed in accordance with standardtechniques, which are well-known to those skilled in the art and asdescribed herein. The use of protecting groups is described in detail inGreen, T. W. and P. G. M. Wutz, Protective Groups in Organic Synthesis(1991), 2nd Ed., Wiley-Interscience.

One of ordinary skill in the art could easily ascertain which choicesfor each substituent are possible for the reaction conditions of eachScheme. Moreover, the substituents are selected from components asindicated in the specification heretofore, and may be attached tostarting materials, intermediates, and/or final products according toschemes known to those of ordinary skill in the art.

Also it will be apparent that the compounds provided herein could existas one or more isomers, that is, E/Z isomers, enantiomers and/ordiastereomers.

Compounds of formula (I) may be generally prepared as depicted in thefollowing schemes, unless otherwise noted, the various substituents areas defined elsewhere herein.

Standard abbreviations and acronyms as defined in J. Org. Chem. 200772(1): 23A-24A are used herein. Other abbreviations and acronyms usedherein are as follows:

AcOH acetic acid DIEA diisopropylethylamine DCM dichloromethane DMAN,N-dimethylacetamide EDCI N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride EtOAc ethyl acetate EtOH ethanol HATUO-(7-azabenzotriazol-1yl)-N,N,N′,N′- tetramethyluroniumhexafluorophosphate HOAc acetic acid LCMS liquid chromatography massspectrometry MeOH methanol t-BuOK potassium tert-butoxide TEATriethylamine

In an illustrative method, certain compounds of formula (I) may beroutinely prepared according to the synthetic route outlined inScheme 1. The readily available 2-amino-substituted azole compounds 1are either commercially available or can be prepared from corresponding4-aminoarylcarboxylates or 4-aminoheteroarylcarboxylates usingprocedures analogous to those described by Molinos-Gomez, et al.Tetrahedron 61, 9075 (2005). Amines 1 can be converted to bromides 2under Sandmeyer conditions with a bromine source such as, but notlimited to, cupric bromide, using an organic nitrite such as, but notlimited to, tert-butyl nitrite or iso-amyl nitrite. The reaction can beconducted in a solvent such as, but not limited to, MeCN. Thecarboxylates of 2 can be reduced to give alcohols 3 using a reducingagent such as, but not limited to, DIBAL-H or LiBH₄, in a solvent suchas, but not limited to, DCM or THF. The alcohols 3 can be converted tosulfonates 4 using a sulfonating agent such as, but not limited to,methanesulfonyl chloride orp-toluenesulfonyl chloride. The reaction canbe conducted in a solvent such as, but not limited to, DCM or THF andpromoted with a base such as, but not limited to, TEA or pyridine.Alkylation of heteroaryls/heterocyclyls 5 with sulfonate 4 to givecompounds 6 can be effected in the presence of a base, such as, but notlimited to, NaH or t-BuOK. The alkylation can be conducted in a solventsuch as, but not limited to, DMF or THF, at elevated temperature ifnecessary. The regiochemistry of the alkylation can be discerned bycareful examination of the 2-dimensional nuclear Overhauser effect (NOE)in the NMR of products. The bromides 6 can be treated with amine 7 undernucleophilic substitution conditions at elevated temperature in asolvent such as, but not limited to, DMA or DMF, and promoted with abase such as, but not limited to, DIEA or TEA to afford compounds 8.

In an illustrative method, certain compounds of formula (I) may beroutinely prepared according to the synthetic route outlined in Scheme2. The readily available aminoaryl/heteroaryl compounds 9 can beconverted to bromides 10 with a bromination agent such as, but notlimited to, N-bromosuccimide or bromine. The reaction can be conductedin a solvent such as, but not limited to, MeCN or DCM. Condensation ofbromides 10 with potassium O-ethyl carbonodithioate in a solvent suchas, but not limited to, DMF under refluxing conditions can affordmercaptan compounds 11, which can be alkylated with iodomethane to givemethylsulfides 12. The reaction can be run in a solvent such as, but notlimited to, DMF or DMA and promoted with a base such as, but not limitedto, K₂CO₃ or Cs₂CO₃ at elevated temperature if necessary. Alternatively,methylsulfides 12 can be prepared starting from bromides 2 by treatingwith sodium thiomethoxide in a solvent, such as, but not limited to, THFor MeCN. The carboxylate group of 12 can be reduced to give alcohols 13using a reducing agent such as, but not limited to, DIBAL-H or LiBH₄, ina solvent such as, but not limited to, DCM or THF. The alcohols 13 canbe converted to chlorides 14 using an agent such as, but not limited to,thionyl chloride or oxalyl chloride, in a solvent such as, but notlimited to, DCM. The reaction can be catalyzed by the addition of asmall amount of DMF. Alkylation of heteroaryls/heterocyclyls 5 withchlorides 14 to give compounds 15 can be effected using a base such as,but not limited to, NaH or t-BuOK. The alkylation can be conducted in asolvent such as, but not limited to, DMF or THF, at elevated temperatureif necessary. The sulfide moiety of 15 can be oxidized to thecorresponding sulfoxide using an oxidizing agent such as, but notlimited to, m-CPBA or peracetic acid. The oxidation can be conducted ina solvent such as, but not limited to, DCM or AcOH. The sulfinyl groupof 16 can be displaced with an amine 7 under nucleophilic substitutionconditions at elevated temperature to afford compounds 8. The reactioncan be run in a solvent such as, but not limited to, DMA or DMF, andpromoted with a base such as, but not limited to, DIEA or TEA.

In another illustrative method, compounds of formula (I) may also beroutinely prepared according to the synthetic route outlined in Scheme3. Heteroaryl bromides 3 can react with amines 7 as previously describedto give products 17, which can be oxidized to the correspondingaldehydes 18 with an oxidizing agent such as, but not limited to,Dess-Martin periodinane or MnO₂, in a solvent such as, but not limitedto, DCM or MeCN. Condensation of aldehydes 18 and heteroaryls 19 canprovide carbinol compounds 20 (R=H). The condensation can be promotedwith a base such as, but not limited to, KOH or NaOH, in a solvent suchas, but not limited to, MeOH or EtOH. When the reaction is conducted inan alcohol solvent, products 20 (R=alkyl) can also be isolated.Reduction of compounds 20 with a silane such as, but not limited to,Et₃SiH, promoted with the addition of an acid such as, but not limitedto, trifluoroacetic acid or methanesulfonic acid will provide compounds21. The reduction reaction can be conducted in a solvent such as, butnot limited to, DCM or MeCN.

In another illustrative method, certain compounds of formula (I) may beroutinely prepared according to the synthetic route outlined in Scheme4. The readily available aminoaryl/heteroaryl nitriles 22 can be treatedwith a halogenating agent such as, but not limited to, N-chlorosuccimideor N-bromosuccimide to afford halogenated products 23. The reaction canbe conducted in a solvent such as, but not limited to, MeCN or DCM.Condensation of compounds 23 with potassium O-ethyl carbonodithioate ina solvent such as, but not limited to, DMF, under refluxing conditionscan afford mercaptan compounds 24, which can be alkylated withiodomethane to give methylsulfides 25. The methylation reaction can beconducted in a solvent such as, but not limited to, DMF or DMA andpromoted with a base such as, but not limited to, K₂CO₃ or Cs₂CO₃, atelevated temperatures if necessary. The nitrile group of 25 can bereduced to aminomethyl compounds 26 using a reducing agent such as, butnot limited to, LiAlH₄ or nickel boride, in a solvent such as, but notlimited to, THF or diethyl ether. Aryl/heteroaryl compounds 27appropriately substituted with halo and nitro groups can react withamines 26 to afford corresponding amino and nitro substitutedaryl/heteroaryl compounds 28, promoted with a base such as, but notlimited to, K₂CO₃ or DIEA, in a solvent such as, but not limited to, DMFor DMA. The reaction can be further promoted by elevated temperatures ifnecessary. The nitro group of 28 can be reduced to an amino group usinga reducing agent such as, but not limited to, Zn or Fe, in the presenceof an acid such as, but not limited to, AcOH or HCl, in a solvent suchas, but not limited to, DCM or EtOH. The diamino heteroaryls 29 canreact with a trialkyl orthoformate such as, but not limited to,trimethyl orthoformate or triethyl orthoformate to form bicyclicheteroaryl compounds 30. The cyclization reaction can be promoted withan acid catalyst such as, but not limited to, HCOOH or AcOH at elevatedtemperature. The sulfides 30 can be converted to sulfoxides 31, then tofinal compounds 32 as described for Scheme 2.

In another illustrative method, compounds of formula (I) may also beroutinely prepared according to the synthetic route outlined in Scheme5. Alkylation of heteroaryls/heterocyclyls 33 with chlorides 14 to givecompounds 34 can be effected using a base such as, but not limited to,NaH or t-BuOK. The alkylation can be conducted in a solvent such as, butnot limited to, DMF or THF, at elevated temperatures if necessary.Following a two step sequence of oxidation and nucleophilic substitutionas described in Scheme 2, the sulfides 34 can be converted first tosulfoxides 35 and then to compounds 36. Suzuki coupling of 36 with arylor heteroaryl boronic acids or boronate esters catalyzed by a palladiumcatalyst such as, but not limited to, Pd(dppf)Cl₂ or PdCl₂(PPh₃)₂, in asolvent such as, but not limited to, MeCN or 1,4-dioxane, can providethe aryl-heteroaryl/biheteroaryl compounds 37. The Suzuki reaction canbe promoted with a base such as, but not limited to, Na₂CO₃ or KOAc, atelevated temperatures as needed. Compounds 36 can also undergoUllmann-type coupling with a NH-containing nucleophile such as, but notlimited to, an amine or carboxamide, to yield compounds 38. The reactioncan be catalyzed with a catalyst such as, but not limited to, copper (I)iodide or copper, promoted with a base such as, but not limited to,K₂CO₃ or Cs₂CO₃, and conducted in a solvent such as, but not limited to,DMF or NMP, at elevated temperature. Alternatively, compounds 34(X=CO₂R) can undergo aminolysis with any of various amines to givecarboxamides 39. The reaction can be promoted with a reagent such as,but not limited to, trimethylaluminum or triethylaluminum, and conductedin a solvent such as, but not limited to, DCE or DCM. Following a twostep sequence of oxidation and nucleophilic substitution as described inScheme 2, compounds 39 can be converted to final compounds 40.

In another illustrative method, compounds of formula (I) may also beroutinely prepared according to the synthetic route outlined in Scheme6. Starting from appropriate aminoaryl/heteroaryl dihalides 41,Sonogashira coupling with ethynyltrimethylsilane catalyzed by a catalystsuch as PdCl₂(PPh₃)₂ or PdCl₂(dppf) can afford the acetylenes 42. Thecoupling reaction can be promoted with a base such as, but not limitedto, DIEA or TEA, and conducted in a solvent such as, but not limited to,DMF or MeCN, at elevated temperatures if necessary. Condensation of 42with potassium O-ethyl carbonodithioate in a solvent such as, but notlimited to, DMF, with heating can afford mercaptan compounds 43, whichcan be alkylated with iodomethane to give methylsulfides 44. Thereaction can be conducted in a solvent such as, but not limited to, DMFor DMA and promoted with bases such as, but not limited to, K₂CO₃ orCs₂CO₃, at elevated temperatures if necessary. Three componentcyclization using acetylenes 44, aminoaryl/heteroaryl compounds 45, andparaformaldehyde in a solvent such as, but not limited to, toluene atelevated temperature provides compounds 46. The cyclization can bepromoted with a catalyst such as, but not limited to, copper (I)chloride and copper (II) triflate. Following a two step sequence ofoxidation and nucleophilic substitution as described in Scheme 2,compounds 46 can be converted to final compounds 47.

In another illustrative method, compounds of formula (I) may also beroutinely prepared according to the synthetic route outlined in Scheme7. Alkylation of heteroaryls 48 (wherein X is connected to W=carbon)with chlorides 14 from Scheme 2 using conditions described in Scheme 2can provide compounds 49. Following a two step sequence of oxidation andnucleophilic substitution as described in Scheme 2, compounds 49 can beconverted to common intermediates 50. As described in Scheme 5, Suzukicoupling of 50 with coupling partners such as, but not limited to,boronic acids, boronate esters, or Molander trifluoroborates can yieldcompounds 51. Ullmann coupling of 50 with NH-containing nucleophilessuch as, but not limited to, amines or carboxamides, under conditionsdescribed for Scheme 5 can lead to compounds 52. Sonogashira coupling of50 with acetylenes under conditions described for Scheme 6 can yieldcompounds 53.

In another illustrative method, compounds of formula (I) may also beroutinely prepared according to the synthetic route outlined in Scheme8. Starting from the common intermediates 50 described in Scheme 7,reduction of the carboxylates of 50 (X=CO₂R) using a reducing agent suchas, but not limited to, DIBAL-H or LiBH₄, in a solvent such as, but notlimited to, DCM or THF, can afford alcohols 54. Stille coupling of 50(X=I, Br, or Cl) with an appropriate tributyl alkoxyvinyl stannanefollowed by acidic hydrolysis can yield the acetyl compounds 55. Thereaction is typically catalyzed by a catalyst such as Pd(PPh₃)₄ andconducted in a solvent such as, but not limited to, DMF or DMA.Similarly, palladium-mediated cyanation of 50 (X=I, Br, or Cl) with areagent such as, but not limited to, Zn(CN)₂, can provide the cyanocompounds 56. The reaction is catalyzed by catalysts such asPdCl₂(PPh₃)₂ or PdCl₂(dppf), promoted with bases such as, but notlimited to, DIEA or TEA, and conducted in solvents such as, but notlimited to, DMF or MeCN, at elevated temperature. Analogously,palladium-mediated sulfonylation of 50 (X=I, Br, or Cl) with a reagentsuch as, but not limited to, sodium methanesulfinate, can generatesulfonyl compounds 57. The reaction is catalyzed by a catalyst such as,but not limited to, copper (I) trifluoromethane-sulfonate benzenecomplex, promoted with an amine such as, but not limited to,unsymmetrical N,N-dimethylethylene diamine, and conducted in a solventsuch as, but not limited to, DMF or DMSO, at elevated temperature. Thecarboxylate of common intermediates 50 (X=CO₂R) can be hydrolyzed usinga base such as, but not limited to, NaOH or KOH, in a solvent such as,but not limited to, MeOH or THF, to give carboxylic acids 58. Couplingof acids 58 with any of various amines using peptide coupling agentssuch as, but not limited to, EDCI or HATU, can afford the carboxamides59. The reaction can be promoted with a base such as, but not limitedto, DIEA or TEA and conducted in a solvent such as, but not limited to,DMF or THF.

In another illustrative method, compounds of formula (I) may also beroutinely prepared according to the synthetic route outlined in Scheme9. Alkylation of amino nitro aryls/heteroaryls 60 with chlorides 14 canbe effected using a base such as, but not limited to, NaH or t-BuOK togive compounds 28. The alkylation can be conducted in a solvent such as,but not limited to, DMF or THF. Alternatively, alcohols 13 can beoxidized to aldehydes 61 using an oxidizing agent such as, but notlimited to, Dess-Martin periodinane or MnO₂, in a solvent such as, butnot limited to, DCM or MeCN. Reductive alkylation of amino nitroaryls/heteroaryls 60 with aldehydes 61 can be effected using a reducingagent such as, but not limited to, NaCNBH₃ or Na(OAc)₃BH, usually in thepresence of an acid such as, but not limited to, TFA or AcOH, to givecompounds 28. The reductive alkylation reaction can be conducted in asolvent such as, but not limited to, DCM or DCE. Compounds 28 can beconverted to the final compounds 32 as described in Scheme 4.

In another illustrative method, compounds of formula (I) may also beroutinely prepared according to the synthetic route outlined in Scheme10. Starting with nitriles 25 from Scheme 4, oxidation of the sulfidemoiety and nucleophilic substitution with amino alcohols such as, butnot limited to, a single stereoisomer of 2-aminocyclohexanol, canprovide the compounds 62. Simultaneous protection of the NH and OHgroups of 62 by treatment with a ketal such as, but not limited to,2,2-dimethoxypropane in the presence of an acid catalyst such as, butnot limited to, p-toluenesulfonic acid or camphorsulfonic acid, in asolvent such as, but not limited to, toluene or 1,4-dioxane, withheating as required can afford compounds 63. Reduction of the nitrilegroup of 63 can be realized using a metal hydride such as, but notlimited to, LiAlH₄ or nickel boride, in a solvent such as THF or diethylether to give amines 64. Using procedures analogous to those describedin Scheme 4 for conversion of compounds 26 to compounds 30, a three stepsequence can convert compounds 64 to compounds 65, after which theprotecting group can be removed using an acid such as, but not limitedto, TFA in DCM or HCl in 1,4-dioxane, to give compounds of the invention66. Compounds 66 can furthermore be oxidized to ketones 67 using anoxidizing agent such as, but not limited to, Dess-Martin periodinane or2-iodoxybenzoic acid, in a solvent such as, but not limited to, DCM orMeCN. Treatment of ketones 67 with hydroxylamine or an alkoxylamine atelevated temperature in a solvent such as, but not limited to, EtOH orMeOH can generate oximes 68. The reaction can be promoted with a basesuch as, but not limited to, pyridine. On the other hand, ketones 67 canreact with organometallic agents such as, but not limited to, Grignardreagents or organolithium agents, in a solvent such as, but not limitedto, THF or diethyl ether, to give compounds 69, which may be formed as amixture of diastereoisomers.

In another illustrative method, compounds of formula (I) may also beroutinely prepared according to the synthetic route outlined in Scheme11. Reaction of nitriles 56 from Scheme 8 with hydroxylamine derivativesat elevated temperature in a solvent such as, but not limited to, EtOHor MeOH can generate hydroxyl or alkoxyl amidines 70. The reaction canbe promoted with a base such as, but not limited to, pyridine. Reactionof nitriles 56 with azide, for example with NaN₃ and NH₄Cl, in a solventsuch as, but not limited to, DMF or DMA, can provide tetrazole compounds71. Alkylation of the tetrazoles with alkyl or haloalkyl halides usingbases such as, but not limited to, K₂CO₃ or Cs₂CO₃, in solvents such as,but not limited to, DMF or DMA, at elevated temperature can yieldtetrazole derivatives 72 and 73. Reduction of the nitrile group of 56can be realized using metal hydrides such as, but not limited to, LiAlH₄or nickel boride, in a solvent such as THF or diethyl ether to giveamino compounds 74. Acylation of the amino group of 74 with an acylatinggroup in the presence of a base such as, but not limited to, pyridine orDIEA, in a solvent such as DCM or DCE, can afford amides 75;corresponding carbamates or ureas can be prepared similarly, by using achloroformate or an isocyanate, respectively, as the acylating agent.

In an illustrative method, the oxazole derivatives used herein may beroutinely prepared according to the synthetic route outlined in Scheme12. Heating of aminophenols 76 with potassium O-ethyl carbonodithioatein solvent such as, but not limited to, pyridine can yield compounds 77.As described in Scheme 2, a three step sequence of alkylation,reduction, and chlorination can generate chloride derivatives 80.Intermediate 78 from the above sequence can alternatively be convertedto nitrile 78a by a standard three-step sequence consisting of esterhydrolysis, primary amide formation, and dehydration. Final oxazolecompounds of the invention can be prepared by substituting oxazoles 79in place of thiazoles 13 in Scheme 9 and conducting the remainder of thesynthetic sequence using procedures analogous to those in Scheme 9;additional final oxazole compounds of the invention can be prepared bysubstituting oxazoles 80 in place of thiazoles 14 in Schemes 2, 5, 7,and 9 and conducting the remainder of the respective synthetic sequencesusing procedures analogous to those in Scheme 2, 5, 7, or 9; andadditional final oxazole compounds of the invention can also be preparedby substituting oxazoles 78a in place of thiazoles 25 in Schemes 4 and10 and conducting the remainder of the respective synthetic sequencesusing procedures analogous to those in Scheme 4 or 10.

In an illustrative method, bicyclic imidazole derivatives used hereinmay be routinely prepared according to the synthetic route outlined inScheme 13. Nitration of amino aryl/heteroaryl compounds 81 can berealized using reagents such as, but not limited to, a mixture ofconcentrated sulfuric acid and nitric acid, to give amino nitrocompounds 82. Reduction of compounds 82 using a reducing agent such as,but not limited to, Zn or Fe in the presence of an acid such as, but notlimited to, AcOH or HCl, in a solvent such as, but not limited to, DCMor EtOH can give diamino compounds 83. Compounds 83 can be converted tobicyclic imidazole derivatives 84 by reaction with an orthoformate suchas, but not limited to, trimethyl orthoformate or triethyl orthoformate.The reaction can be promoted with an acid catalyst such as, but notlimited to, HCOOH or AcOH at elevated temperature.

In an illustrative method, amino alcohol derivatives used herein may beroutinely prepared according to the synthetic route outlined in Scheme14. Cycloalkenes 85 can be oxidized using reagents such as, but notlimited to, mCPBA or NaOCl to give epoxides 86, which can react with anazide such as, but not limited to, TMSN₃ or n-Bu₄NN₃, in a solvent suchas, but not limited to, THF or DCM, to give azido alcohols 87. The azidogroup of 87 can be reduced to an amino group using hydrogenation orStaudinger reduction conditions to afford amino alcohols 88.

In another illustrative method, amino alcohol derivatives used hereinmay also be routinely prepared according to the synthetic route outlinedin Scheme 15. Amino acids 89 and 91 can be reduced to amino alcohols 90and 92, respectively, using a reagent such as, but not limited to,LiAlH₄ or diborane, in a solvent such as THF or diethyl ether.Similarly, cyanohydrins 93 can be reduced to amino alcohols 94 using ametal hydride such as, but not limited to, LiAlH₄ or nickel boride, in asolvent such as THF or diethyl ether.

In an illustrative method, certain 5-membered heteroaryl derivativesused herein may be routinely prepared according to the synthetic routeoutlined in Scheme 16. Heteroaryls 95 containing an appropriate halosubstituent can be protected with a protecting group such as, but notlimited to, trimethylsilylethoxymethylene group, to give compounds 96.The protection can be effected using a base such as, but not limited to,NaH or t-BuOK, and conducted in a solvent such as, but not limited to,DMF or THF, at elevated temperature if necessary. Haloheteroarylcompounds 96 can undergo Suzuki coupling as described in Scheme 5 withcoupling partners such as, but not limited to, boronic acids, boronateesters, or Molander trifluoroborates to yield compounds 97. Subsequentremoval of the protecting group using a reagent such as, but not limitedto, TFA in DCM or HCl in 1,4-dioxane can provide heteroaryl derivatives98. Similarly, Ullmann-type coupling of 96 with NH-containingnucleophiles such as, but not limited to, amine or carboxamides, canlead to compounds 99, from which the protecting group can be removed asabove to afford heteroaryl derivatives 100.

In an illustrative method, certain 6-membered heteroaryl/heterocyclylderivatives used herein may be routinely prepared according to thesynthetic route outlined in Scheme 17. Halogenatedheteroaryl/heterocyclyl compounds 101 can undergo Suzuki coupling asdescribed in Scheme 5 with coupling partners such as, but not limitedto, boronic acids, boronate esters, or Molander trifluoroborates toyield compounds 102. Subsequent alkaline hydrolysis with, for example,KOH or NaOH, in a solvent such as, but not limited to, DMSO or THF canprovide heterocyclyl derivatives 103. Similarly, Ullmann-type couplingof halides 101 with a NH-containing nucleophile such as, but not limitedto, an amine or carboxamide, can lead to compounds 104, from whichsubsequent hydrolysis can lead to heteroaryl/heterocyclyl derivatives105.

In an illustrative method, compounds of formula (I) may also beroutinely prepared according to the synthetic route outlined in Scheme18. The readily available aminoaryl/heteroaryl derivatives 106 and 106acan react with potassium O-ethyl carbonodithioate in solvent such as,but not limited to, DMF or pyridine with heating to give fused mercaptanderivatives 107. Methylation of compounds 107 can be realized using MeIpromoted with a base such as, but not limited to, K₂CO₃ or Cs₂CO₃ in asolvent such as, but not limited to, DMF or DMA, to give compounds 108.Heck coupling of halides 108 with allyl alcohol catalyzed with apalladium-based catalyst such as, but not limited to, Pd(OAc)₂ orPd(dba)₂ provides the propanals 109. The reaction can be promoted with apalladium ligand such as, but not limited to, P(o-tolyl)₃ or As(PPh₃)₃and accelerated with a base such as, but not limited to, NaHCO₃ orKHCO₃. The reaction can be conducted in a solvent such as, but notlimited to, MeCN or DMF. Chlorination of propanals 109 can be effectedusing a chlorinating agent such as, but not limited to,N-chlorosuccinimide and catalyzed with an amine such as, but not limitedto, L-proline or piperidine to give chlorides 110. Condensation ofcompounds 110 with six-membered 2-amino heteroaryl derivatives 111 atelevated temperature promoted with a base such as, but not limited to,NaHCO₃ or triethylamine in a solvent such as, but not limited to, n-BuOHor DMF yields bicyclic heteroaryls 112. The sulfides of 112 can beoxidized to sulfoxides using an oxidizing agent such as, but not limitedto, m-CPBA or peracetic acid. The oxidation can be conducted in solventsuch as, but not limited to, DCM or AcOH. Sulfoxides 113 may react withamines 7 under nucleophilic substitution conditions at elevatedtemperature to afford compounds 114. The reaction can be conducted in asolvent such as, but not limited to, DMA or NMP and promoted with a basesuch as, but not limited to, DIEA or TEA.

In an illustrative method, compounds of formula (I) may also beroutinely prepared according to the synthetic route outlined in Scheme19. Condensation of compounds 110 from Scheme 18 with five-memberedaminoheteroaryl derivatives 115 at elevated temperature promoted with abase such as, but not limited to, NaHCO₃ or triethylamine in a solventsuch as, but not limited to, n-BuOH or DMF yields bicyclic heteroaryls116. Using procedures analogous to those described in Scheme 18,oxidation of compounds 116 to give sulfoxides 117, followed by reactionwith amines 7 provides compounds 118.

In an illustrative method, compounds of formula (I) may also beroutinely prepared according to the synthetic route outlined in Scheme20. Sulfides 108 from Scheme 18 can be oxidized to sulfoxides 119 usingan oxidizing agent such as, but not limited to, m-CPBA or peraceticacid, as described in Scheme 18. Reaction of sulfoxides 119 with amines7 provides compounds 120, using a procedure analogous to that describedin Scheme 18. Heck coupling of halides 120 with allyl alcohol yieldspropanals 121, using a procedure analogous to that described in Scheme18. Chlorination of 121 using NCS affords compounds 122. Condensation ofcompounds 122 with six-membered aminoheteroaryl derivatives 111 givescompounds 114, using procedures analogous to those described in Scheme18. Alternatively, condensation of chloroaldehydes 122 with bicyclicamino heteroaryls 123 provides tricyclic compounds 124.

In an illustrative method, compounds of formula (I) may also beroutinely prepared according to the synthetic route outlined in Scheme21. Amino nitro aryls/heteroaryls 82 from Scheme 13 can be converted toformamides 125 when heated in acetic formic mixed anhydride. Alkylationof formamides 125 with chlorides 14 or 80 yields compounds 126. Thealkylation reaction is promoted with a base such as, but not limited to,NaH or t-BuOK in a solvent such as, but not limited to, DMF or THF.Reduction of the nitro group to an amino group, accompanied bycyclization to compounds 127 may be effected utilizing a reducing agentsuch as, but not limited to, iron or zinc, in the presence of an acidsuch as, but not limited to, AcOH or trifluoroacetic acid. The reactionis conducted in a solvent such as, but not limited to, EtOH or MeOH andmay be promoted by heating at elevated temperature. Compound 127 can beconverted to the requisite compounds 32 using procedures analogous tothose described in Scheme 18 for conversion of 112 to 114.

In an illustrative method, compounds of formula (I) may also beroutinely prepared according to the synthetic route outlined in Scheme22. The benzyl groups of compounds 128, which are prepared by methodsdescribed above, are removed using a reagent such as, but not limitedto, BBr₃ or TMSI in a solvent such as, but not limited to, DCM or CH₃CN,to give hydroxyl compounds 129. The vicinal amino alcohol functionalityof 129 is protected, for example as an acetonide, by reacting with areagent such as, but not limited to, 2,2-dimethoxypropane to givecompounds 130. The reaction is catalyzed by acid such as, but notlimited to, p-toluenesulfonic acid or camphor sulfonic acid in a solventsuch as, but not limited to, 1,4-dioxane or toluene. Alkylation of thehydroxyl group of 130 with alkyl halides is promoted with a base suchas, but not limited to, Cs₂CO₃ or NaH in a solvent such as, but notlimited to, NMP or THF to afford ethers 131. Deprotection of 131 withacid such as, but not limited to, HCl or trifluoroacetic acid in asolvent such as, but not limited to, DCM or CH₃CN provides compounds132.

In an illustrative method, compounds of formula (I) may also beroutinely prepared according to the synthetic route outlined in Scheme23. Compounds 133, prepared as described above, can be converted tochlorides 134 by the treatment with sulfuryl chloride in a solvent suchas, but not limited to, DCM or CH₃CN. Analogously, compounds 135 can beconverted to chlorides 136 under the similar conditions. Furthermore,treatment of compounds 135 with an agent such as, but not limited to,diethylaminosulfur trifluoride (DAST) or Deoxo-fluor in a solvent suchas, but not limited to, DCM, can afford cyclohexenes 137.Dihydroxylation at the isolated double bond of 137 with OsO₄ andN-methylmorpholine oxide (NMO) in a solvent such as, but not limited to,H₂O/acetone/t-BuOH provides diol compounds 138 and 139.

In an illustrative method, compounds of formula (I) may also beroutinely prepared according to the synthetic route outlined in Scheme24. Compounds 20 (R=H) from Scheme 3 can be oxidized to ketones 140 witha reagent, such as, but not limited to, Dess-Martin periodinane or Jonesreagent in a solvent such as, but not limited to, CH₃CN or acetone.Ketals 141 can be prepared by heating ketones 140 with an alcohol ordiol in a solvent such as, but not limited to, toluene or benzene. Thereaction can be catalyzed with an acid such as, but not limited to,p-toluene sulfonic acid or camphorsulfonic acid. Ketones 140 can also bebis-fluorinated to give compounds 142 using a fluorinating reagent suchas, but not limited to, diethylaminosulfur trifluoride (DAST) orDeoxo-Fluor. Alcohols 20 can also be converted to fluorides 142a using afluorinating reagent, such as, but not limited to, diethylaminosulfurtrifluoride (DAST) or Deoxo-Fluor.

In an illustrative method, the compounds of formula (I) may also beroutinely prepared according to the synthetic route outlined in Scheme25. Compounds 13 from Scheme 2 can be oxidized to aldehydes 143 with areagent such as, but not limited to, Dess-Martin periodinane, in asolvent such as, but not limited to, CH₃CN or DCM. Meanwhile, readilyavailable compounds 144 can be brominated with a reagent such as, butnot limited to, bromine or N-bromosuccimide to give compounds 145.Trans-metallation of 145 with a reagent such as, but not limited to,n-butyl lithium followed by treatment with aldehydes 143 can yieldalcohols 146, which can be converted to compounds 147 using proceduresanalogous to those described in Scheme 4 for conversion of 30 to 32. Thealcohols 147 can further be converted to ketones 148, fluorides 150a,ketals 149, and difluoro compounds 150 using procedures analogous tothose described in Scheme 24.

The subject matter has been described in an illustrative manner, and itis to be understood that the terminology used is intended to be in thenature of description rather than of limitation. Thus, it will beappreciated by those of skill in the art that conditions such as choiceof solvent, temperature of reaction, volumes, reaction time may varywhile still producing the desired compounds. In addition, one of skillin the art will also appreciate that many of the reagents provided inthe following examples may be substituted with other suitable reagents.See, e.g., Smith & March, Advanced Organic Chemistry, 5^(th) ed. (2001).Such changes and modifications, including without limitation thoserelating to the chemical structures, substituents, derivatives,intermediates, syntheses, formulations and/or methods of use providedherein, may be made without departing from the spirit and scope thereof.U.S. patents and publications referenced herein are incorporated byreference.

EXAMPLES Example 1 Preparation of2-((6-((1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: 6-((1H-Benzo[d]imidazol-1-yl)methyl)-2-bromobenzo[d]thiazole(150 mg, 44%) was obtained as a white solid using a procedure analogousto that described in Step 5 of Example 2, substituting1H-benzo[d]imidazole for 5,6-dimethoxy-1H-benzo[d]imidazole used inExample 2. ¹H NMR (300 MHz, DMSO-d₆) δ 8.45 (s, 1H), 8.06 (s, 1H), 7.97(d, J=8.5 Hz, 1H), 7.62-7.72 (m, 1H), 7.45-7.58 (m, 2H), 7.13-7.28 (m,2H), 5.65 (s, 2H). LCMS (ESI) m/z 344, 346 (M+H)⁺.

Step 2:2-((6-((1H-Benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolwas obtained as a white solid (12 mg, 22%) using a procedure analogousto that described in Step 4 of Example 2, substituting6-((1H-benzo[d]imidazol-1-yl)methyl)-2-bromobenzo[d]thiazole from Step 1of this Example for2-bromo-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole,and racemic trans-2-aminocyclohexanol for (1R,2R)-2-aminocyclohexanolused in Example 2. ¹H NMR (300 MHz, DMSO-d₆) δ 8.40 (s, 1H), 7.98 (d,J=7.5 Hz, 1H), 7.61-7.69 (m, 2H), 7.49-7.59 (m, 1H), 7.25-7.34 (m, 1H),7.13-7.24 (m, 3H), 5.46 (s, 2H), 4.75 (br s, 1H), 3.47-3.59 (m, 2H),2.02 (d, J=10.9 Hz, 1H), 1.87 (d, J=9.2 Hz, 1H), 1.61 (br s, 2H),1.04-1.36 (m, 4H). LCMS (ESI) m/z 379 (M+H)⁺.

Example 2 Preparation of(1R,2R)-2-((6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: To a solution of tert-butyl nitrite (4.5 mL, 37.5 mmol) andcopper(II) bromide (6.0 g, 27 mmol) in CH₃CN (100 mL) at rt was added amixture of ethyl 2-aminobenzo[d]thiazole-6-carboxylate (5.0 g, 22.5mmol) in CH₃CN (50 mL). The reaction suspension was stirred at rt for 1h. The resulting reaction mixture was quenched with 300 mL of 1 N HClaqueous solution and extracted with CH₂Cl₂ (3×200 mL). The combinedorganic layers were dried over MgSO₄, and concentrated under reducedpressure. The crude product was purified on a silica gel column using amixture of CH₂Cl₂-hexanes (4:1, v/v) as eluent to give ethyl2-bromobenzo[d]thiazole-6-carboxylate as a white solid (6.2 g, 96%). ¹HNMR (300 MHz, CDCl₃) δ 8.54 (d, J=1.1 Hz, 1H), 8.16 (dd, J=1.5, 8.7 Hz,1H), 8.02 (d, J=8.7 Hz, 1H), 4.43 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.2 Hz,3H). LCMS (ESI) m/z 288, 286 (M+H)⁺.

Step 2: To a solution of ethyl 2-bromobenzo[d]thiazole-6-carboxylate(5.0 g, 17.5 mmol) from Step 1 of this Example in anhydrous CH₂Cl₂ wasadded DIBAL-H (1.0 M in CH₂Cl₂, 36.7 mL, 36.7 mmol) slowly at −78° C.The solution was stirred at −78° C. for 2 h. The resulting mixture wasquenched with 10 mL of saturated aq sodium potassium tartrate at −78° C.After slowly warming to 0° C., the mixture was further treated with 50mL of saturated aq sodium potassium tartrate and stirred at rt for 2 h.The aqueous layer was separated and extracted with CH₂Cl₂ (3×100 mL).The combined organic layers were washed with brine, dried over MgSO₄,and concentrated under reduced pressure. The crude product was purifiedon a silica gel column using a mixture of EtOAc-hexanes (2:3, v/v) aseluent to give (2-bromobenzo[d]thiazol-6-yl)methanol as a white solid(3.4 g, 80%). ¹H NMR (300 MHz, CDCl₃) δ 7.96 (d, J=8.3 Hz, 1H), 7.85 (s,1H), 7.45 (dd, J=1.4, 8.4 Hz, 1H), 4.83 (s, 2H), 1.86 (br s, 1H). LCMS(ESI) m/z 244, 246 (M+H)⁺.

Step 3: To a solution of (2-bromobenzo[d]thiazol-6-yl)methanol (205 mg,0.83 mmol) from Step 2 of this Example and DIEA (118 mg, 0.92 mmol) inCH₂Cl₂ (20 mL) cooled in an ethylene glycol-water (4:1, v/v) dry icebath was added methanesulfonyl chloride (105 mg, 0.92 mmol) slowly. Thereaction solution was warmed to rt and stirred at rt for 1 h. Theresulting mixture was quenched with 20 mL of water. The separatedaqueous layer was extracted with CH₂Cl₂ (3×20 mL). The combined organiclayers were washed with brine, dried over MgSO₄, and concentrated underreduced pressure to give (2-bromobenzo[d]thiazol-6-yl)methylmethanesulfonate as a light yellow solid (267 mg, 100%). LCMS (ESI) m/z322, 324 (M+H)⁺.

Step 4: To a solution of (2-bromobenzo[d]thiazol-6-yl)methylmethanesulfonate (460 mg, 1.4 mmol) from Step 3 of this Example in DMF(5 mL) was added 5,6-dimethoxy-1H-benzo[d]imidazole (560 mg, 3.14 mmol)portion wise at rt. The mixture was stirred at rt overnight. Theresulting solution was diluted with 40 mL of EtOAc and washed withwater, brine. The separated organic layer was dried over MgSO₄, andconcentrated under reduced pressure The crude product was purified on asilica gel column using a mixture of MeOH—CH₂Cl₂ (1:20, v/v) as eluentto give2-bromo-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazoleas a light yellow solid (427 mg, 75%). LCMS (ESI) m/z 404, 406 (M+H)⁺.

Step 5: To a suspension of2-bromo-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole(202 mg, 0.5 mmol) from Step 4 of this Example in DMA (4 mL) were addedDIEA (129 mg, 1.0 mmol) and (1R,2R)-2-aminocyclohexanol (69 mg, 0.6mmol) at rt. The mixture was stirred in a sealed tube at 120° C.overnight. After cooling to rt, the mixture was concentrated underreduced pressure. The crude product was purified by HPLC using a mixtureof water (5% CH₃CN, 0.05% AcOH) and CH₃CN (0.05% AcOH) as the mobilephase and Varian Pursuit XRs Diphenyl column as the stationary phase toafford(1R,2R)-2-((6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolas a white solid (127 mg, 58%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.14 (s,1H), 7.99 (d, J=7.5 Hz, 1H), 7.62 (s, 1H), 7.04-7.34 (m, 4H), 5.40 (s,2H), 4.77 (br s, 1H), 3.76 (s, 6H), 3.51 (br s, 1H), 1.77-2.14 (m, 3H),1.61 (br, 2H), 1.04-1.38 (m, 4H). LCMS (ESI) m/z 439 (M+H)⁺.

Example 3 Preparation of(1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolmethanesulfonic acid

Step 1: To a solution of ethyl 2-bromobenzo[d]thiazole-6-carboxylate(4.8 g, 16.8 mmol) from Step 1 of Example 2 in THF (100 mL) was addedsodium thiomethoxide (1.74 g, 25.2 mmol) slowly at 0° C. The reactionmixture was stirred at rt overnight. The mixture was diluted with Et₂O(200 mL) and washed with saturated aq NaHCO₃ and brine. The organiclayer was dried over MgSO₄ and concentrated under reduced pressure togive ethyl 2-(methylthio)benzo[d]thiazole-6-carboxylate as a white solid(4.18 g, 98%). ¹H NMR (300 MHz, CDCl₃) δ 8.48 (d, J=1.5 Hz, 1H), 8.11(dd, J=1.6, 8.6 Hz, 1H), 7.87 (d, J=8.5 Hz, 1H), 4.41 (q, J=7.1 Hz, 2H),2.82 (s, 3H), 1.42 (t, J=7.1 Hz, 3H) LCMS (ESI) m/z 254 (M+H)⁺.

Step 2: (2-(Methylthio)benzo[d]thiazol-6-yl)methanol (4.1 g, 88%) wasobtained as a white solid using a procedure analogous to that describedin Step 2 of Example 2, substituting ethyl2-(methylthio)benzo[d]thiazole-6-carboxylate from Step 1 of this Examplefor ethyl 2-bromobenzo[d]thiazole-6-carboxylate used in Example 2. LCMS(ESI) m/z 212 (M+H)⁺.

Step 3: To a solution of (2-(methylthio)benzo[d]thiazol-6-yl)methanol(4.1 g, 19.4 mmol) from Step 2 of this Example and DIEA (3.26 g, 25.3mmol) in CH₂Cl₂ (200 mL) was added methanesulfonyl chloride (2.88 g,25.3 mmol) slowly at 0° C. The mixture was then treated with 2 drops ofDMF and stirred at rt overnight. The mixture was quenched with 300 mL ofsaturated aq NaHCO₃. The separated aqueous layer was extracted withCH₂Cl₂ (2×250 mL). The combined organic layers were washed with brine,dried over MgSO₄, and concentrated under reduced pressure to give6-(chloromethyl)-2-(methylthio)benzo[d]thiazole as a light brown solid(4.4 g, 99%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.10 (d, J=1.5 Hz, 1H), 7.84(d, J=8.5 Hz, 1H), 7.53 (dd, J=1.6, 8.4 Hz, 1H), 4.89 (s, 2H), 2.80 (s,3H). LCMS (ESI) m/z 231 (M+H)⁺.

Step 4: To a solution of 3H-imidazo[4,5-b]pyridine (2.99 g, 25 mmol) inDMF (100 mL) was added sodium hydride (60% in mineral oil, 1.0 g, 25mmol) slowly at 0° C. After the reaction mixture was stirred at rt for20 min, it was treated with a solution of6-(chloromethyl)-2-(methylthio)benzo[d]thiazole from Step 3 of thisExample (4.8 g, 21 mmol) in DMF (20 mL) at 0° C. The reaction mixturewas then stirred at rt overnight. The mixture was quenched with 3 mL ofsaturated aq NH₄Cl and concentrated under reduced pressure. The residuewas diluted with 600 mL of EtOAc and washed with water and brine. Theorganic layer was dried over MgSO₄ and concentrated under reducedpressure The crude product was purified on a silica gel column using amixture of MeOH—CH₂Cl₂ (1:30, v/v) as eluent to give6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazoleas a tan solid (2.5 g, 38%). The regiochemistry of the alkylation wasdetermined by a 2-dimensional nuclear Overhauser effect (NOE)experiment. ¹H NMR (300 MHz, DMSO-d₆) δ 8.65 (s, 1H), 8.38 (dd, J=1.2,4.8 Hz, 1H), 8.11 (dd, J=1.3, 8.1 Hz, 1H), 8.00 (d, J=1.1 Hz, 1H), 7.81(d, J=8.3 Hz, 1H), 7.46 (dd, J=1.6, 8.4 Hz, 1H), 7.30 (dd, J=4.8, 8.0Hz, 1H), 5.62 (s, 2H), 2.77 (s, 3H). LCMS (ESI) m/z 313 (M+H)⁺.

Step 5: To a solution of6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole(2.5 g, 8 mmol) in CH₂Cl₂ (150 mL) was added mCPBA (70%, 2.36 g, 9.6mmol) slowly at 0° C. The mixture was stirred at rt overnight. Theresulting solution was diluted with 150 mL CH₂Cl₂ and washedsequentially with saturated aq Na₂S₂O₃, saturated aq NaHCO₃ and brine.The organic layer was dried over MgSO₄, and concentrated under reducedpressure to give6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazoleas a white solid (2.6 g, 99%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.68 (s, 1H),8.37 (dd, J=1.3, 4.7 Hz, 1H), 8.23 (d, J=0.9 Hz, 1H), 7.99-8.18 (m, 2H),7.63 (dd, J=1.7, 8.5 Hz, 1H), 7.30 (dd, J=4.7, 8.1 Hz, 1H), 5.70 (s,2H), 3.06 (s, 3H). LCMS (ESI) m/z 339 (M+H)⁺.

Step 6: To a suspension of6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole(1.3 g, 3.96 mmol) from Step 5 of this Example in DMA (6 mL) were addedDIEA (511 mg, 3.96 mmol) and (1R,2R)-2-aminocyclohexanol (1.36 g, 11.9mmol) at rt. The reaction mixture was stirred in a sealed tube at 120°C. for 6 h. After cooling to rt, the mixture was diluted with 120 mL ofEtOAc and washed with 120 mL of water. The organic layer was dried overMgSO₄ and concentrated under reduced pressure. The crude product waspurified on a silica gel column using a mixture of acetone-EtOAc (1:12,v/v) as eluent to give(1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolas an off white solid (864 mg, 58%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.60(s, 1H), 8.38 (dd, J=1.3, 4.7 Hz, 1H), 8.09 (dd, J=1.2, 8.0 Hz, 1H),7.95 (d, J=7.5 Hz, 1H), 7.67 (s, 1H), 7.17-7.35 (m, 3H), 5.49 (s, 2H),4.73 (d, J=5.3 Hz, 1H), 3.52 (d, J=8.5 Hz, 1H), 3.32 (br s, 1H),1.76-2.12 (m, 2H), 1.61 (br s, 2H), 1.07-1.38 (m, 4H). LCMS (ESI) m/z380 (M+H)⁺.

Step 7: To a suspension of(1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(1.84 g, 4.88 mmol) in EtOH (100 mL) was added methanesulfonic acid (478mg, 4.98 mmol) at rt. The reaction mixture was stirred at 55° C. for 2h. After cooling to rt, the mixture was concentrated under reducedpressure. The residue was diluted with 15 mL of water and freeze driedovernight to give(1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolmethanesulfonate as a tan solid (2.32 g, 100%). ¹H NMR (300 MHz,MeOH-d₄) δ 8.80 (s, 1H), 8.50 (dd, J=1.1, 4.7 Hz, 1H), 8.15 (dd, J=1.1,8.1 Hz, 1H), 7.82 (s, 1H), 7.36-7.59 (m, 3H), 5.68 (s, 2H), 3.40-3.65(m, 2H), 2.71 (s, 3H), 2.06 (d, J=12.2 Hz, 2H), 1.79 (d, J=6.6 Hz, 2H),1.24-1.55 (m, 4H). LCMS (ESI) m/z 380 (M+H)⁺.

Example 4 Preparation of a mixture of(1R,2R)-2-((6-((6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanoland(1R,2R)-2-((6-((5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: A mixture of2-bromo-6-((6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazoleand2-bromo-6-((5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole(846 mg, 81%) was obtained as white solid using a procedure analogous tothat described in Step 4 of Example 2, substituting6-methoxy-1H-benzo[d]imidazole for 5,6-dimethoxy-1H-benzo[d]imidazoleused in Example 2. LCMS (ESI) m/z 374, 376 (M+H)⁺.

Step 2: A mixture of(1R,2R)-2-((6-((6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanoland(1R,2R)-2-((6-((5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(119 mg, 51%) was obtained as a white solid using a procedure analogousto that described in Step 5 of Example 2, substituting the mixture of2-bromo-6-((6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazoleand2-bromo-6-((5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazolefrom Step 1 of this Example for2-bromo-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazoleused in Example 2. ¹H NMR (300 MHz, DMSO-d₆) δ 8.31 (s, 1H), 8.24 (s,1H), 7.98 (d, J=7.3 Hz, 2H), 7.58-7.69 (m, 2H), 7.52 (d, J=8.7 Hz, 1H),7.35-7.46 (m, 1H), 7.25-7.34 (m, 2H), 7.06-7.24 (m, 4H), 6.82 (ddd,J=2.3, 6.8, 8.8 Hz, 2H), 5.42 (s, 4H), 4.78 (br s, 2H), 3.76 (d, J=2.3Hz, 6H), 3.51 (br s, 3H), 3.27-3.40 (m, 2H), 1.77-2.18 (m, 4H), 1.62 (d,J=5.1 Hz, 4H), 1.04-1.42 (m, 7H). LCMS (ESI) m/z 409 (M+H)⁺.

Example 5 Preparation of(1R,2R)-2-((6-((1H-imidazo[4,5-b]pyridin-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: To a solution of (2-bromobenzo[d]thiazol-6-yl)methylmethanesulfonate (900 mg, 2.79 mmol) from Step 3 of Example 2 and1H-imidazo[4,5-b]pyridine (365 mg, 3.07 mmol) in DMF (8 mL) was addedpotassium carbonate (560 mg, 3.14 mmol) at rt. The reaction mixture wasstirred at rt overnight. It was then diluted with 80 mL of EtOAc and theresulting mixture was washed with water and brine. The organic layer wasseparated and dried over MgSO₄, and concentrated under reduced pressure.The crude product was purified on a silica gel column using a mixture ofMeOH—CH₂Cl₂ (1:20, v/v) as eluent to give three isomers:

Isomer 16-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)-2-bromobenzo[d]thiazole

¹H NMR (300 MHz, DMSO-d₆) δ 8.67 (s, 1H), 8.37 (dd, J=1.3, 4.7 Hz, 1H),8.12 (dd, J=1.2, 8.0 Hz, 1H), 8.06 (d, J=0.9 Hz, 1H), 7.93-8.00 (m, 1H),7.55 (dd, J=1.5, 8.5 Hz, 1H), 7.31 (dd, J=4.8, 8.0 Hz, 1H), 5.67 (s,2H). NOESY: a-b, a-c, a-d. LCMS (ESI) m/z 345, 347 (M+H)⁺.

Isomer 26-((1H-Imidazo[4,5-b]pyridin-1-yl)methyl)-2-bromobenzo[d]thiazole

¹H NMR (300 MHz, DMSO-d₆) δ 8.72 (s, 1H), 8.42 (dd, J=1.5, 4.7 Hz, 1H),8.08 (d, J=0.9 Hz, 1H), 7.99 (td, J=1.7, 8.1 Hz, 2H), 7.50-7.60 (m, 1H),7.25 (dd, J=4.7, 8.1 Hz, 1H), 5.70 (s, 2H). NOESY: a-b, a-c, a-d, a-e.LCMS (ESI) m/z 345, 347 (M+H)⁺.

Isomer 36-((4H-Imidazo[4,5-b]pyridin-4-yl)methyl)-2-bromobenzo[d]thiazole

¹H NMR (300 MHz, DMSO-d₆) δ 8.42-8.51 (m, 1H), 8.28-8.40 (m, 2H), 8.20(d, J=0.9 Hz, 1H), 7.99 (d, J=8.5 Hz, 1H), 7.68 (dd, J=1.6, 8.4 Hz, 1H),7.21-7.35 (m, 1H), 6.04 (s, 2H). NOESY: a-b, a-c, a-f LCMS (ESI) m/z345, 347 (M+H)⁺.

Step 2:(1R,2R)-2-((6-((1H-Imidazo[4,5-b]pyridin-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(41 mg, 42%) was obtained as a white solid using a procedure analogousto that described in Step 5 of Example 2, substituting the6-((1H-imidazo[4,5-b]pyridin-1-yl)methyl)-2-bromobenzo[d]thiazole(Isomer 2) from Step 1 of this Example for2-bromo-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazoleused in Example 2. ¹H NMR (300 MHz, DMSO-d₆) δ 8.66 (s, 1H), 8.35-8.44(m, 1H), 8.00 (d, J=7.0 Hz, 2H), 7.69 (s, 1H), 7.12-7.36 (m, 3H), 5.50(s, 2H), 4.77 (br s, 1H), 3.24-3.40 (m, 2H), 2.02 (d, J=10.2 Hz, 1H),1.87 (d, J=9.4 Hz, 1H), 1.62 (d, J=4.9 Hz, 2H), 1.22 (d, J=6.0 Hz, 4H).LCMS (ESI) m/z 380 (M+H)⁺.

Example 6 Preparation of(1R,2R)-2-((6-((1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

To a suspension of6-((1H-benzo[d]imidazol-1-yl)methyl)-2-bromobenzo[d]thiazole from Step 1of Example 1 (34.4 mg, 0.1 mmol) in DMA (3 mL) were added DIEA (15 mg,0.12 mmol) and (1R,2R)-2-aminocyclohexanol (13.8 mg, 0.12 mmol) at rt.The reaction mixture was stirred in a sealed tube at 120° C. overnight.After cooling to rt, the mixture was concentrated under reducedpressure. The crude product was purified by preparative HPLC using amixture of water (containing 5% CH₃CN, 0.05% HCOOH) and CH₃CN(containing 0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18column as the stationary phase to afford(1R,2R)-2-((6-((1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(22 mg, 58%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.40 (s, 1H),7.99 (d, J=7.3 Hz, 1H), 7.60-7.72 (m, 2H), 7.55 (dd, J=2.6, 6.0 Hz, 1H),7.26-7.34 (m, 1H), 7.12-7.25 (m, 3H), 5.47 (s, 2H), 4.76 (br s, 1H),3.26-3.39 (m, 2H), 2.03 (d, J=10.0 Hz, 1H), 1.87 (d, J=9.4 Hz, 1H), 1.62(d, J=4.7 Hz, 2H), 1.03-1.39 (m, 4H). LCMS (ESI) m/z 379 (M+H)⁺.

Example 7 Preparation of(1S,2S)-2-((6-((1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

(1S,2S)-2-((6-((1H-Benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(27 mg, 71%) was obtained as a white solid using a procedure analogousto that described in Example 6, substituting (1S,2S)-2-aminocyclohexanolfor (1R,2R)-2-aminocyclohexanol used in Example 6. ¹H NMR (300 MHz,DMSO-d₆) δ 8.40 (s, 1H), 8.03 (d, J=7.3 Hz, 1H), 7.60-7.72 (m, 2H), 7.55(dd, J=2.6, 6.0 Hz, 1H), 7.25-7.34 (m, 1H), 7.11-7.24 (m, 3H), 5.46 (s,2H), 4.82 (br s, 1H), 3.50 (br s, 2H), 1.82-2.15 (m, 2H), 1.61 (br s,2H), 1.02-1.41 (m, 4H). LCMS (ESI) m/z 379 (M+H)⁺.

Example 8 Preparation of(R)-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-N-((tetrahydrofuran-2-yl)methyl)benzo[d]thiazol-2-amine

(R)-6-((5,6-Dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-N-((tetrahydrofuran-2-yl)methyl)benzo[d]thiazol-2-amine(33 mg, 65%) was obtained as a white solid using a procedure analogousto that described in Step 5 of Example 2, substituting(R)-(tetrahydrofuran-2-yl)methanamine for (1R,2R)-2-aminocyclohexanolused in Example 2. ¹H NMR (300 MHz, DMSO-d₆) δ 8.05-8.22 (m, 2H), 7.64(d, J=1.1 Hz, 1H), 7.27-7.37 (m, 1H), 7.11-7.25 (m, 3H), 5.41 (s, 2H),3.95-4.07 (m, 1H), 3.70-3.83 (m, 7H), 3.57-3.68 (m, 2H), 3.43-3.52 (m,1H), 1.72-2.00 (m, 3H), 1.48-1.64 (m, 1H). LCMS (ESI) m/z 425 (M+H)⁺.

Example 9 Preparation of6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-N-(pyridin-2-ylmethyl)benzo[d]thiazol-2-amine

6-((5,6-Dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-N-(pyridin-2-ylmethyl)benzo[d]thiazol-2-amine(31 mg, 60%) was obtained as a white solid using a procedure analogousto that described in Step 5 of Example 2, substitutingpyridin-2-ylmethanamine for (1R,2R)-2-aminocyclohexanol used in Example2. ¹H NMR (300 MHz, DMSO-d₆) δ 8.67 (t, J=5.5 Hz, 1H), 8.52 (d, J=4.3Hz, 1H), 8.15 (s, 1H), 7.56-7.85 (m, 2H), 7.05-7.46 (m, 6H), 5.42 (s,2H), 4.67 (d, J=5.3 Hz, 2H), 3.76 (s, 6H). LCMS (ESI) m/z 432 (M+H)⁺.

Example 10 Preparation of(1R,2S)-1-((6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol

(1R,2S)-1-((6-((5,6-Dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol(27 mg, 39%) was obtained as a white solid using a procedure analogousto that described in Step 5 of Example 2, substituting(1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol for(1R,2R)-2-aminocyclohexanol used in Example 2. ¹H NMR (300 MHz, DMSO-d₆)δ 8.33 (d, J=8.5 Hz, 1H), 8.16 (s, 1H), 7.69 (s, 1H), 7.31-7.39 (m, 1H),7.10-7.29 (m, 7H), 5.35-5.50 (m, 3H), 4.53-4.63 (m, 1H), 3.77 (d, J=3.2Hz, 6H), 3.08 (dd, J=4.8, 16.1 Hz, 2H), 2.83 (d, J=16.0 Hz, 1H). LCMS(ESI) m/z 473 (M+H)⁺.

Example 11 Preparation of(S)—N-(2,3-dihydro-1H-inden-1-yl)-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-amine

(S)—N-(2,3-dihydro-1H-inden-1-yl)-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-amine(22 mg, 33%) was obtained as a white solid using a procedure analogousto that described in Step 5 of Example 2, substituting(S)-2,3-dihydro-1H-inden-1-amine for (1R,2R)-2-aminocyclohexanol used inExample 2. ¹H NMR (300 MHz, DMSO-d₆) δ 8.43 (d, J=7.9 Hz, 1H), 8.17 (s,1H), 7.68 (d, J=0.9 Hz, 1H), 7.05-7.46 (m, 7H), 5.35-5.53 (m, 3H), 3.77(d, J=2.6 Hz, 2H), 3.36 (s, 6H), 2.74-3.08 (m, 2H), 1.79-2.02 (m, 1H).LCMS (ESI) m/z 457 (M+H)⁺.

Example 12 Preparation of(1R,2R)-2-((6-(methoxy(1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: To a suspension of (2-bromobenzo[d]thiazol-6-yl)methanol (400mg, 1.6 mmol) from Step 2 of Example 2 in DMA (6 mL) were added DIEA(258 mg, 2.0 mmol) and (1R,2R)-2-aminocyclohexanol (226 mg, 2.0 mmol) atrt. The reaction mixture was stirred in a sealed tube at 120° C.overnight. After cooling to rt, the mixture was concentrated underreduced pressure to give crude(1R,2R)-2-((6-(hydroxymethyl)benzo[d]thiazol-2-yl)amino)cyclohexanol asa brown oil (445 mg, 100%), which was used for the next step without anyfurther purification. LCMS (ESI) m/z 279 (M+H)⁺.

Step 2: To a solution of(1R,2R)-2-((6-(hydroxymethyl)benzo[d]thiazol-2-yl)amino)cyclohexanolfrom Step 1 of this Example (445 mg, 1.6 mmol) in CH₂Cl₂ (40 mL) wasadded manganese(IV) oxide (696 mg, 8.0 mmol) at rt. The reactionsuspension was heated under reflux overnight. After cooling to rt, thereaction mixture was filtered through a Celite pad. The filtrate wasconcentrated under reduced pressure to give crude2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazole-6-carbaldehyde asa brown oil (440 mg, 99%), which was used to next step without furtherpurification. LCMS (ESI) m/z 277 (M+H)⁺.

Step 3: To a solution of 1H-pyrrolo[2,3-b]pyridine (205 mg, 1.74 mmol)in MeOH (20 mL) were added potassium hydroxide (162 mg, 2.9 mmol) and2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazole-6-carbaldehydefrom Step 2 of this Example (400 mg, 1.45 mmol) sequentially at rt. Thereaction mixture was stirred at rt for 14 d. The resulting mixture wasdiluted with EtOAc (80 mL) and washed with water, brine. The organiclayer was dried over MgSO₄, and concentrated under reduced pressure. Thecrude product was purified by HPLC using a mixture of water (5% CH₃CN,0.05% HCOOH) and CH₃CN (0.05% HCOOH) as the mobile phase and VarianPursuit XRs C-18 column as the stationary phase to afford(1R,2R)-2-((6-(methoxy(1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolas a white solid (32 mg, 5.4%). ¹H NMR (300 MHz, CDCl₃) δ 9.70 (br s,1H), 8.26 (dd, J=1.4, 4.8 Hz, 1H), 7.85 (dd, J=1.3, 7.7 Hz, 1H), 7.64(d, J=1.3 Hz, 1H), 7.44-7.54 (m, 1H), 7.34 (d, J=8.3 Hz, 1H), 6.97-7.11(m, 2H), 5.64 (br s, 1H), 5.56 (s, 1H), 3.44-3.67 (m, 3H), 3.42 (s, 3H),2.06-2.27 (m, 2H), 1.65-1.87 (m, 2H), 1.14-1.53 (m, 4H). LCMS (ESI) m/z409 (M+H)⁺.

Example 13 Preparation ofN-benzyl-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-amine

N-Benzyl-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-amine(21 mg, 33%) was obtained as a white solid using a procedure analogousto that described in Step 5 of Example 2, substituting phenylmethanaminefor (1R,2R)-2-aminocyclohexanol used in Example 2. ¹H NMR (300 MHz,DMSO-d₆) δ 8.54 (t, J=5.7 Hz, 1H), 8.15 (s, 1H), 7.66 (d, J=1.3 Hz, 1H),7.07-7.47 (m, 9H), 5.41 (s, 2H), 4.57 (d, J=5.7 Hz, 2H), 3.76 (s, 6H).LCMS (ESI) m/z 431 (M+H)⁺.

Example 14 Preparation of6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-N-(2-morpholinoethyl)benzo[d]thiazol-2-amine

6-((5,6-Dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-N-(2-morpholinoethyl)benzo[d]thiazol-2-amine(14 mg, 21%) was obtained as a white solid using a procedure analogousto that described in Step 5 of Example 2, substituting2-morpholinoethanamine for (1R,2R)-2-aminocyclohexanol used in Example2. ¹H NMR (300 MHz, DMSO-d₆) δ 8.15 (s, 1H), 7.99 (t, J=5.0 Hz, 1H),7.64 (s, 1H), 7.27-7.36 (m, 1H), 7.11-7.26 (m, 3H), 5.41 (s, 2H), 3.76(s, 6H), 3.52-3.66 (m, 4H), 3.38-3.51 (m, 4H), 2.33-2.45 (m, 4H). LCMS(ESI) m/z 454 (M+H)⁺.

Example 15 Preparation of6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazol-2-amine

6-((5,6-Dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-N-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazol-2-amine(34 mg, 54%) was obtained as a white solid using a procedure analogousto that described in Step 5 of Example 2, substitutingtetrahydro-2H-pyran-4-amine for (1R,2R)-2-aminocyclohexanol used inExample 2. ¹H NMR (300 MHz, DMSO-d₆) δ 8.15 (s, 1H), 8.09 (d, J=7.2 Hz,1H), 7.65 (d, J=1.1 Hz, 1H), 7.30-7.37 (m, 1H), 7.13-7.25 (m, 3H), 5.41(s, 2H), 3.81-4.00 (m, 2H), 3.76 (s, 6H), 3.37-3.51 (m, 3H), 1.93 (d,J=10.5 Hz, 2H), 1.37-1.56 (m, 2H). LCMS (ESI) m/z 425 (M+H)⁺.

Example 16 Preparation ofN-cyclohexyl-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-N-methylbenzo[d]thiazol-2-amine

N-Cyclohexyl-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-N-methylbenzo[d]thiazol-2-amine(47 mg, 73%) was obtained as a white solid using a procedure analogousto that described in Step 5 of Example 2, substitutingN-methylcyclohexanamine for (1R,2R)-2-aminocyclohexanol used in Example2. ¹H NMR (300 MHz, DMSO-d₆) δ 8.16 (s, 1H), 7.75 (d, J=1.1 Hz, 1H),7.37 (d, J=8.3 Hz, 1H), 7.24 (dd, J=1.5, 8.3 Hz, 1H), 7.18 (d, J=3.0 Hz,2H), 5.43 (s, 2H), 3.88 (br s, 1H), 3.76 (s, 6H), 2.98 (s, 3H),1.47-1.90 (m, 7H), 1.35 (q, J=12.5 Hz, 2H), 1.03-1.22 (m, 1H). LCMS(ESI) m/z 437 (M+H)⁺.

Example 17 Preparation of(1R,2R)-2-((6-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

To a solution of(1R,2R)-2-((6-(methoxy(1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(20 mg, 0.049 mmol) from Step 3 of Example 12 in CH₃CN (10 mL) wereadded triethylsilane (11.4 mg, 0.092 mmol) and TFA (10.4 mg, 0.092 mmol)at rt. The mixture was stirred at 60° C. overnight. After cooling to rt,the reaction mixture was concentrated under reduced pressure. The crudeproduct was purified by HPLC using a mixture of water (5% CH₃CN, 0.05%AcOH) and CH₃CN (0.05% AcOH) as the mobile phase and Varian Pursuit XRsDiphenyl column as the stationary phase to afford(1R,2R)-2-((6-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(5.7 mg, 31%) as a brown solid. ¹H NMR (300 MHz, DMSO-d₆) δ 11.71 (br s,1H), 9.56 (br s, 1H), 8.23 (d, J=4.1 Hz, 1H), 7.93 (d, J=7.0 Hz, 1H),7.70 (s, 1H), 7.26-7.42 (m, 3H), 7.07 (dd, J=4.9, 7.9 Hz, 1H), 4.11 (s,2H), 3.53 (br s, 1H), 3.27-3.43 (m, 2H), 1.83-2.12 (m, 2H), 1.66 (br s,2H), 1.27 (br s, 4H). LCMS (ESI) m/z 379 (M+H)⁺.

Example 18 Preparation ofN-cyclohexyl-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-amine

N-Cyclohexyl-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-amine(41 mg, 66%) was obtained as a white solid using a procedure analogousto that described in Step 5 of Example 2, substituting cyclohexanaminefor (1R,2R)-2-aminocyclohexanol used in Example 2. ¹H NMR (300 MHz,DMSO-d₆) δ 8.15 (s, 1H), 7.97 (d, J=7.5 Hz, 1H), 7.63 (s, 1H), 7.27-7.36(m, 1H), 7.08-7.25 (m, 3H), 5.40 (s, 2H), 3.76 (s, 6H), 3.60-3.71 (m,1H), 1.95 (d, J=10.4 Hz, 2H), 1.49-1.80 (m, 3H), 1.06-1.46 (m, 5H). LCMS(ESI) m/z 423 (M+H)⁺.

Example 19 Preparation of(1R,2R)-1-((6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol

(1R,2R)-1-((6-((5,6-Dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol(41 mg, 66%) was obtained as a white solid using a procedure analogousto that described in Step 5 of Example 2, substituting(1R,2R)-1-amino-2,3-dihydro-1H-inden-2-ol for(1R,2R)-2-aminocyclohexanol used in Example 2. ¹H NMR (300 MHz, DMSO-d₆)δ 8.49 (d, J=7.9 Hz, 1H), 8.17 (s, 1H), 7.69 (s, 1H), 7.32-7.43 (m, 1H),7.05-7.31 (m, 7H), 5.44 (s, 2H), 5.18 (t, J=6.9 Hz, 1H), 4.30 (q, J=6.9Hz, 1H), 3.77 (d, J=3.0 Hz, 6H), 3.38 (br s, 1H), 3.16 (dd, J=7.0, 15.4Hz, 1H), 2.75 (dd, J=7.2, 15.4 Hz, 1H). LCMS (ESI) m/z 473 (M+H)⁺.

Example 20 Preparation of(1R,2R)-2-((6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclopentanol

(1R,2R)-2-((6-((5,6-Dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclopentanol(31 mg, 49%) was obtained as a white solid using a procedure analogousto that described in Step 5 of Example 2, substituting(1R,2R)-2-aminocyclopentanol for (1R,2R)-2-aminocyclohexanol used inExample 2. ¹H NMR (300 MHz, DMSO-d₆) δ 8.15 (s, 1H), 8.05 (d, J=6.6 Hz,1H), 7.64 (d, J=1.1 Hz, 1H), 7.28-7.37 (m, 1H), 7.11-7.26 (m, 3H), 5.41(s, 2H), 4.95 (br. s., 1H), 3.91-4.03 (m, 1H), 3.81-3.91 (m, 1H), 3.76(s, 6H), 1.75-1.94 (m, 2H), 1.56-1.74 (m, 2H), 1.39-1.55 (m, 2H). LCMS(ESI) m/z 425 (M+H)⁺.

Example 21 Preparation of6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-N-(pyridin-4-ylmethyl)benzo[d]thiazol-2-amine

6-((5,6-Dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-N-(pyridin-4-ylmethyl)benzo[d]thiazol-2-amine(29 mg, 45%) was obtained as a white solid using a procedure analogousto that described in Step 5 of Example 2, substitutingpyridin-4-ylmethanamine for (1R,2R)-2-aminocyclohexanol used in Example2. ¹H NMR (300 MHz, DMSO-d₆) δ 8.67 (t, J=5.8 Hz, 1H), 8.50 (d, J=5.7Hz, 2H), 8.15 (s, 1H), 7.68 (d, J=0.9 Hz, 1H), 7.06-7.42 (m, 6H), 5.42(s, 2H), 4.62 (d, J=5.5 Hz, 2H), 3.76 (s, 6H). LCMS (ESI) m/z 432(M+H)⁺.

Example 22 Preparation of6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-N-phenylbenzo[d]thiazol-2-amine

To a suspension of2-bromo-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole(60 mg, 0.148 mmol) from Step 4 of Example 2 in aniline (0.6 mL) wasadded DIEA (23 mg, 0.178 mmol) at rt. The reaction mixture was stirredin a sealed tube at 120° C. for 48 h. After cooling to rt, the reactionmixture was concentrated under reduced pressure. The crude product waspurified by HPLC using a mixture of water (5% CH₃CN, 0.05% HCOOH) andCH₃CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18column as the stationary phase to afford6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-N-phenylbenzo[d]thiazol-2-amine(31 mg, 50%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.53 (br s,1H), 8.18 (s, 1H), 7.71-7.82 (m, 3H), 7.56 (d, J=8.3 Hz, 1H), 7.26-7.42(m, 3H), 7.19 (d, J=3.2 Hz, 2H), 7.01 (t, J=7.3 Hz, 1H), 5.48 (s, 2H),3.77 (s, 6H). LCMS (ESI) m/z 417 (M+H)⁺.

Example 23 Preparation of(1R,2R)-2-((6-((5-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: To a stirred solution of 4-aminobenzonitrile (10.0 g, 84.7 mmol)in MeCN (100 mL) at 90° C. was slowly added N-chlorosuccinimide (12.4 g,93 mmol). After the addition of N-chlorosuccinimide, the reactionmixture was stirred at 90° C. for 2 h. The reaction mixture was thencooled to rt and concentrated under reduced pressure. The residue wasdissolved in 500 mL of CH₂Cl₂ and washed with 5% aq NaOH. The organiclayer was dried over MgSO₄ and concentrated under reduced pressure togive 4-amino-3-chlorobenzonitrile as a tan solid (12.2 g, 95%). ¹H NMR(300 MHz, CDCl₃) δ 7.54 (d, J=1.7 Hz, 1H), 7.35 (dd, J=1.8, 8.4 Hz, 1H),6.77 (d, J=8.5 Hz, 1H), 4.63 (br s, 2H).

Step 2: To a solution of 4-amino-3-chlorobenzonitrile (12.2 g, 80.2mmol) from Step 1 of this Example in DMF (60 mL) was added potassiumO-ethyl carbonodithioate (28.9 g, 180.7 mmol) at rt. The mixture wasrefluxed for 4 h. After cooling to rt, the reaction mixture was pouredinto ice water and acidified with 2N aq HCl. The tan solids werecollected and dried in vacuum oven overnight. Then the solids wererefluxed with 500 mL of CHCl₃ for 10 min. After cooling to rt, themixture was treated with 200 mL of hexanes and sonicated for 20 min. Thepale brown solid was collected by filtration to give2-mercaptobenzo[d]thiazole-6-carbonitrile (12.9 g, 84%). ¹H NMR (300MHz, DMSO-d₆) δ 14.16 (br s, 1H), 8.23 (d, J=0.9 Hz, 1H), 7.83 (dd,J=1.3, 8.5 Hz, 1H), 7.31-7.51 (m, 1H).

Step 3: Sodium hydride (60% in mineral oil, 1.92 g, 48 mmol) wassuspended in DMF (60 mL) at 0° C. and2-mercaptobenzo[d]thiazole-6-carbonitrile (5.76 g, 30 mmol) from Step 2of this Example was added slowly. After gas evolution ceased,iodomethane (8.4 mL, 135 mmol) was added and the reaction mixture wasstirred at rt overnight. To the reaction mixture was added 300 mL ofwater and the precipitate was collected by filtration to give2-(methylthio)benzo[d]thiazole-6-carbonitrile as a light yellow solid(5.47 g, 89%). ¹H NMR (300 MHz, CDCl₃) δ 8.08 (d, J=1.1 Hz, 1H), 7.91(d, J=8.3 Hz, 1H), 7.67 (dd, J=1.5, 8.5 Hz, 1H), 2.83 (s, 3H).

Step 4: To a solution of 2-(methylthio)benzo[d]thiazole-6-carbonitrile(10.0 g, 48.5 mmol) from Step 3 of this Example in THF (150 mL) wasadded lithium aluminum hydride solution (2.0 M in THF, 50.9 mL, 101.9mmol) slowly at −78° C. The reaction mixture was slowly warmed to 0° C.and stirred at 0° C. for 3 h treated with 4 mL of water, 4 mL of 10% aqNaOH and 12 mL of water. The resulting reaction mixture was stirred atrt for 1 h before it was filtered through a Celite pad and theprecipitates were washed with 100 of mL EtOAc. The combined filtrateswere concentrated under reduced pressure. The crude product was purifiedon a silica gel column using a mixture of MeOH—CH₂Cl₂ (1:2, v/v) aseluent to give (2-(methylthio)benzo[d]thiazol-6-yl)methanamine as anyellow oil (3.5 g, 34%). ¹H NMR (300 MHz, CDCl₃) δ 7.82 (d, J=8.3 Hz,1H), 7.73 (s, 1H), 7.35 (dd, J=1.4, 8.4 Hz, 1H), 3.97 (s, 2H), 2.79 (s,3H), 1.55 (s, 2H). LCMS (ESI) m/z 211 (M+H)⁺.

Step 5: To a solution of 2-chloro-6-methoxy-3-nitropyridine (430 mg, 2.3mmol) in DMF (6 mL) was added(2-(methylthio)benzo[d]thiazol-6-yl)methanamine (437 mg, 2.1 mmol) fromStep 4 of this Example slowly at 0° C. The reaction mixture was stirredat rt overnight. The resulting reaction mixture was diluted with 60 mLof EtOAc and washed with saturated aq NaHCO₃ and brine. The organiclayer was dried over MgSO₄, and concentrated under reduced pressure. Thecrude product was purified on a silica gel column using CH₂Cl₂ as eluentto give6-methoxy-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3-nitropyridin-2-amineas a yellow solid (431 mg, 57%). LCMS (ESI) m/z 363 (M+H)⁺.

Step 6: To a mixture of6-methoxy-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3-nitropyridin-2-amine(431 mg, 1.19 mmol) from Step 5 of this Example in acetic acid (6 mL)was added zinc powder (235 mg, 3.57 mmol) slowly at 0° C. The reactionmixture was stirred at 0° C. for 20 min and then stirred at rt for 4 h.The resulting reaction mixture was diluted with 30 mL of EtOAc andfiltered through a Celite pad. The filtrate was neutralized withsaturated aq NaHCO₃. The organic layer was separated, dried over MgSO₄,and concentrated under reduced pressure. The crude product was purifiedon a silica gel column using a mixture of EtOAc—CH₂Cl₂ (1:3, v/v) aseluent to give6-methoxy-N²-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyridine-2,3-diamineas a brown oil (389 mg, 98%). LCMS (ESI) m/z 333 (M+H)⁺.

Step 7: To a solution of triethoxymethane (5 mL) was added6-methoxy-N²-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyridine-2,3-diamine(332 mg, 1.0 mmol) from Step 6 of this Example at rt. The reactionmixture was heated under reflux overnight. After cooling to rt, themixture was concentrated under reduced pressure. The crude product waspurified on a silica gel column using a mixture of EtOAc—CH₂Cl₂ (0 to100%, v/v) as eluent to give6-((5-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazoleas a brown solid (180 mg, 53%). ¹H NMR (300 MHz, CDCl₃) δ 7.95 (d, J=8.7Hz, 1H), 7.87 (s, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.70 (d, J=1.1 Hz, 1H),7.41 (dd, J=1.7, 8.3 Hz, 1H), 6.71 (d, J=8.7 Hz, 1H), 5.47 (s, 2H), 3.99(s, 3H), 2.78 (s, 3H). LCMS (ESI) m/z 343 (M+H)⁺.

Step 8:(6-((5-Methoxy-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole(180 mg, 100%) was obtained as an off white solid using a procedureanalogous to that described in Step 5 of Example 3, substituting6-((5-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazolefrom Step 7 of this Example for6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazoleused in Example 3. LCMS (ESI) m/z 359 (M+H)⁺.

Step 9:(1R,2R)-2-((6-((5-Methoxy-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(36 mg, 35%) was obtained as a white solid using a procedure analogousto that described in Step 5 of Example 2, substituting6-((5-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole from Step 8 of this Example for2-bromo-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazoleused in Example 2. ¹H NMR (300 MHz, DMSO-d₆) δ 8.34 (s, 1H), 7.90-8.08(m, 2H), 7.73 (s, 1H), 7.29 (s, 2H), 6.69 (d, J=8.5 Hz, 1H), 5.39 (s,2H), 4.76 (br s, 1H), 3.94 (s, 3H), 3.51 (br s, 2H), 1.76-2.17 (m, 2H),1.61 (br s, 2H), 1.04-1.42 (m, 4H). LCMS (ESI) m/z 410 (M+H)⁺.

Example 24 Preparation of1-(4-((6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)piperidin-1-yl)ethanoneacetic acid

A stirred mixture of2-bromo-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole(80 mg, 0.198 mmol) from Example 2, 1-(4-aminopiperidin-1-yl)ethanone(56 mg, 0.396 mmol) and DIEA (77 mg, 0.594 mmol) in anhydrous DMA (1 mL)was heated at 120° C. for 15 h. After cooling to rt, the mixture waspurified directly by reverse-phase HPLC using a mixture of water (5%CH₃CN, 0.05% HCOOH) and CH₃CN (0.05% HCOOH) as the mobile phase andVarian Pursuit XRs C-18 column as the stationary phase to afford1-(4-((6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)piperidin-1-yl)ethanoneacetate (7 mg, 7%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.15(s, 1H), 8.08 (d, J=7.2 Hz, 1H), 7.65 (s, 1H), 7.30-7.37 (m, 1H),7.14-7.25 (m, 3H), 5.41 (s, 2H), 4.18 (m, 1H), 3.94 (m, 1H), 3.75-3.77(m, 7H), 3.11-3.24 (m, 2H), 2.78-2.85 (m, 1H), 1.95-2.05 (m, 4H), 1.89(s, 3H), 1.19-1.48 (m, 2H). LCMS (ESI) m/z 466 (M+H)⁺.

Example 25 Preparation of(R,S)-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-N-(tetrahydrofuran-3-yl)benzo[d]thiazol-2-amineacetic acid

A stirred mixture of2-bromo-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole(80 mg, 0.198 mmol) from Example 2, (R,S)-tetrahydrofuran-3-amine (34mg, 0.396 mmol) and DIEA (77 mg, 0.594 mmol) in anhydrous DMA (1 mL) washeated at 120° C. for 3 h. After cooling to rt, the mixture was purifieddirectly by reverse-phase HPLC using a mixture of water (5% CH₃CN, 0.05%HCOOH) and CH₃CN (0.05% HCOOH) as the mobile phase and Varian PursuitXRs C-18 column as the stationary phase to afford(R,S)-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-N-(tetrahydrofuran-3-yl)benzo[d]thiazol-2-amineacetate (15 mg, 16%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.28(d, J=6.0 Hz, 1H), 8.15 (s, 1H), 7.66 (d, J=1.1 Hz, 1H), 7.36 (d, J=8.1Hz, 1H), 7.14-7.26 (m, 3H), 5.42 (s, 2H), 4.39 (br s, 1H), 3.59-3.88 (m,11H), 2.12-2.26 (m, 1H), 1.88 (s, 3H). LCMS (ESI) m/z 411 (M+H)⁺.

Example 26 Preparation of3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-2-aminiumacetic acid

Step 1:3-((2-Bromobenzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-2-amine(34 mg, 20%) was obtained as a white solid using a procedure analogousto that described in Step 4 of Example 2, substituting3H-imidazo[4,5-b]pyridin-2-amine for 5,6-dimethoxy-1H-benzo[d]imidazoleused in Example 2. ¹H NMR (300 MHz, CDCl₃): δ 7.97 (d, J=8.5 Hz, 1H),7.51 (d, J=5.5 Hz, 2H), 7.35 (dd, J=8.3, 1.5 Hz, 1H), 7.14-7.23 (m, 1H),7.05-7.14 (m, 3H), 5.28 (s, 2H).

Step 2:(1R,2R)-2-((6-((2-Amino-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(14 mg, 36%) was obtained as a white solid using a procedure analogousto that described in Step 5 of Example 2, substituting3-((2-bromobenzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-2-aminefrom Step 1 of this Example for2-bromo-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazoleused in Example 2. ¹H NMR (300 MHz, DMSO-d₆) δ 7.95 (d, J=7.5 Hz, 1H),7.48 (d, J=1.1 Hz, 1H), 7.27 (d, J=8.3 Hz, 1H), 7.02-7.19 (m, 3H), 6.91(t, J=7.1 Hz, 1H), 6.76-6.85 (m, 1H), 6.54 (s, 2H), 5.22 (s, 2H), 4.77(br. s., 1H), 3.11 (br. s., 2H), 1.95-2.16 (m, 2H), 1.87 (s, 3H), 1.62(d, J=4.5 Hz, 2H), 1.01-1.41 (m, 4H). LCMS (ESI) m/z 395 (M+H)⁺.

Example 27 Preparation of6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-N-(2-ethoxyphenyl)benzo[d]thiazol-2-amine

To a suspension of2-bromo-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole(60 mg, 0.15 mmol) from Example 2 and 2-ethoxyaniline (61 mg, 0.46 mmol)in anhydrous DMA (600 μL) at rt was added DIEA (155 μL, 0.90 mmol). Themixture was heated in a sealed tube at 110° C. for 72 h. After coolingto rt, the resulting reaction solution was purified by reverse-phasepreparative HPLC using a mixture of water (5% CH₃CN, 0.05% HCOOH) andCH₃CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18column as the stationary phase to afford6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-N-(2-ethoxyphenyl)benzo[d]thiazol-2-amine(15.2 mg, 22%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.69 (s,1H), 8.31-8.44 (m, 1H), 8.18 (s, 1H), 7.76 (d, J=1.1 Hz, 1H), 7.51 (d,J=8.1 Hz, 1H), 7.29 (dd, J=1.5, 8.3 Hz, 1H), 7.19 (d, J=2.4 Hz, 2H),6.91-7.07 (m, 3H), 5.47 (s, 2H), 4.12 (q, J=6.8 Hz, 2H), 3.76 (s, 6H),1.37 (t, J=7.0 Hz, 3H). LCMS (ESI) m/z 461 (M+H)⁺.

Example 28 Preparation ofN-(cyclohexylmethyl)-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-amine

A stirred mixture of2-bromo-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole(70 mg, 0.173 mmol) from Example 2, cyclohexanemethylamine (39 mg, 0.346mmol) and DIEA (67 mg, 0.519 mmol) in anhydrous DMA (1.5 mL) was heatedat 100° C. for 2.5 h. After cooling to rt, the mixture was purifieddirectly by reverse-phase HPLC using a mixture of water (5% CH₃CN, 0.05%HCOOH) and CH₃CN (0.05% HCOOH) as the mobile phase and Varian PursuitXRs C-18 column as the stationary phase to affordN-(cyclohexylmethyl)-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-amine(25 mg, 33%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.15 (br s,1H), 8.04 (t, J=5.4 Hz, 1H), 7.63 (s, 1H), 7.31 (m, 1H), 7.12-7.24 (m,3H), 5.40 (s, 2H), 3.76 (s, 6H), 3.17 (t, J=6.1 Hz, 2H), 1.49-1.78 (m,6H), 1.07-1.27 (m, 3H), 0.84-1.02 (m, 2H). LCMS (ESI) m/z 437 (M+H)⁺.

Example 29 Preparation of(1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1:5-Bromo-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3-nitropyridin-2-amine(605 mg, 44%) was obtained as a yellow solid using a procedure analogousto that described in Step 5 of Example 23, substituting5-bromo-2-chloro-3-nitropyridine for 2-chloro-6-methoxy-3-nitropyridineused in Example 23. LCMS (ESI) m/z 409, 411 (M+H)⁺.

Step 2:5-Bromo-N²-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyridine-2,3-diamine(170 mg, 30%) was obtained as an yellow oil using a procedure analogousto that described in Step 6 of Example 23, substituting5-bromo-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3-nitropyridin-2-aminefrom Step 1 of this Example for6-methoxy-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3-nitropyridin-2-amineused in Example 23. LCMS (ESI) m/z 381, 383 (M+H)⁺.

Step 3:6-((6-Bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole(71 mg, 40%) was obtained as an off white solid using a procedureanalogous to that described in Step 7 of Example 23, substituting5-bromo-N²-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyridine-2,3-diaminefrom Step 2 of this Example for6-methoxy-N²-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyridine-2,3-diamineused in Example 23. LCMS (ESI) m/z 391, 393 (M+H)⁺.

Step 4:6-((6-Bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole(73 mg, 100%) was obtained as an off white solid using a procedureanalogous to that described in Step 8 of Example 23, substituting6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazolefrom Step 3 of this Example for6-((5-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazoleused in Example 23. LCMS (ESI) m/z 407, 409 (M+H)⁺.

Step 5:(1R,2R)-2-((6-((6-Bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(22 mg, 27%) was obtained as a white solid using a procedure analogousto that described in Step 5 of Example 2, substituting6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole from Step 4 of this Example for2-bromo-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazoleused in Example 2. ¹H NMR (300 MHz, DMSO-d₆) δ 8.66 (s, 1H), 8.48 (d,J=2.1 Hz, 1H), 8.40 (d, J=2.1 Hz, 1H), 8.00 (d, J=7.5 Hz, 1H), 7.65 (s,1H), 7.15-7.36 (m, 2H), 5.48 (s, 2H), 4.78 (br s, 1H), 3.51 (br s, 1H),1.96-2.13 (m, 1H), 1.87 (d, J=9.6 Hz, 1H), 1.61 (br s, 2H), 1.01-1.40(m, 4H). LCMS (ESI) m/z 458, 460 (M+H)⁺.

Example 30 Preparation of6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-N-(2-methoxyphenyl)benzo[d]thiazol-2-amine

To a suspension of2-bromo-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole(26 mg, 0.063 mmol) from Example 2 and 2-methoxyaniline (15.5 mg, 0.13mmol) in anhydrous 1,4-dioxane (0.30 mL) at rt was added Cs₂CO₃ (41 mg,0.13 mmol). Argon was bubbled into the mixture for 5 min followed by theaddition of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3.0 mg,0.005 mmol) and tris(dibenzylideneacetone)dipalladium (0) (2.3 mg, 0.003mmol). Argon was bubbled into the mixture for an additional 5 min andthen the mixture was heated in a sealed tube at 100° C. for 4 h. Aftercooling to rt, the reaction mixture was filtered through a Celite plugand the filtrate was purified by reverse-phase preparative HPLC using amixture of water (5% CH₃CN, 0.05% HCOOH) and CH₃CN (0.05% HCOOH) as themobile phase and Varian Pursuit XRs C18 column as the stationary phaseto afford6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-N-(2-methoxyphenyl)benzo[d]thiazol-2-amine(9.4 mg, 33%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.85 (s,1H), 8.42 (d, J=7.3 Hz, 1H), 8.18 (s, 1H), 7.76 (d, J=1.1 Hz, 1H), 7.51(d, J=8.1 Hz, 1H), 7.28 (dd, J=1.5, 8.3 Hz, 1H), 7.19 (d, J=2.1 Hz, 2H),6.92-7.09 (m, 3H), 5.46 (s, 2H), 3.86 (s, 3H), 3.76 (d, J=0.8 Hz, 6H).LCMS (ESI) m/z 447 (M+H)⁺.

Example 31 Preparation of2-((6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)phenol

To a suspension of2-bromo-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole(70 mg, 0.17 mmol) from Example 2 and 2-aminophenol (95 mg, 0.87 mmol)in anhydrous DMA (300 μL) at rt was added DIEA (90 μL, 0.52 mmol). Themixture was stirred and heated in a sealed tube at 110° C. for 96 h.After cooling to rt, the mixture was purified by reverse-phasepreparative HPLC using a mixture of water (5% CH₃CN, 0.05% HCOOH) andCH₃CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18column as the stationary phase to afford2-((6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)phenol(12 mg, 16%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.77 (br s,1H), 8.14-8.26 (m, 2H), 7.75 (s, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.24-7.29(m, 1H), 7.16-7.22 (m, 2H), 6.79-6.92 (m, 3H), 5.46 (s, 2H), 3.76 (s,6H). LCMS (ESI) m/z 461 (M+H)⁺.

Example 32 Preparation of(1R,2R)-1-((6-((4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-olor(1R,2R)-1-((6-((5-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-olAlternative of Example 83

Step 1: To a stirred mixture of DMF (15 mL) and NaH (60% dispersion inmineral oil, 539 mg, 21 mmol) at 0° C. under argon was added4-bromo-1H-imidazole (3 g, 20 mmol) in one portion. The mixture wasstirred for 5 min at 0° C. A solution of 2-(trimethylsilyl)ethoxymethylchloride (4.3 mL, 24 mmol) in DMF (3 mL) was added dropwise. Afterstirring at 0° C. for 1 h, the mixture was warmed slowly to rt andstirred for 6 h. The mixture was then partitioned between EtOAc (100 mL)and water (50 mL). The EtOAc layer was separated and washed with brine,dried over Na₂SO₄, filtered, and the filtrate was concentrated underreduced pressure. The residue was purified via silica gel flashchromatography (eluting with a gradient of 100% hexanes to 100% EtOAc)to afford a regioisomeric mixture of4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole and5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole as an oil (2.9g, 53%). LCMS (ESI) m/z 277 and 279 (M+H)⁺.

Step 2: To a mixture of4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole and5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (345 mg, 1.3mmol) from Step 1 of this Example, and 1-methylpyrazole-4-boronic acidpinacol ester (390 mg, 1.9 mmol) in DME (3 mL) was added K₂CO₃ (691, 5mmol). Argon was bubbled into the mixture for 5 min followed by theaddition of Pd(PPh₃)₂Cl₂ (44 mg, 0.06 mmol). Argon was bubbled into themixture for an additional 5 min. Then the reaction vessel was sealed andthe mixture was heated at 100° C. for 15 h. The mixture was cooled tort, then partitioned between EtOAc (100 mL) and water (50 mL). The EtOAclayer was separated and washed with brine, dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified viasilica gel flash chromatography eluting with a gradient of 100% CH₂Cl₂to 10% MeOH in CH₂Cl₂ to afford a regioisomeric mixture of1-methyl-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-1H-pyrazoleand1-methyl-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-1H-pyrazoleas an oil (280 mg, 82%). LCMS (ESI) m/z 280 (M+H)⁺.

Step 3: A mixture of1-methyl-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-1H-pyrazoleand1-methyl-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-1H-pyrazole(170 mg, 0.7 mmol) from Step 2 of this Example were stirred in a 1:1mixture of TFA and CH₂Cl₂ (5 mL) for 15 h. The mixture was thenconcentrated under reduced pressure to afford4-(1H-imidazol-4-yl)-1-methyl-1H-pyrazole (248 mg) as an oil and wasused in the next step without further purification. LCMS (ESI) m/z 149(M+H)⁺.

Step 4: To a stirred mixture of6-(chloromethyl)-2-(methylthio)benzo[d]thiazole (209 mg, 0.9 mmol) fromStep 4 of Example 36 and 4-(1H-imidazol-4-yl)-1-methyl-1H-pyrazole (248mg, 1.0 mmol) from Step 3 of this Example, in anhydrous DMF (3.0 mL) wasadded K₂CO₃ (700 mg, 5 mmol). After stirring for 3 h at 80° C., thereaction mixture was cooled to rt and partitioned between EtOAc (150 mL)and water (50 mL). The EtOAc layer was separated, washed with brine (50ml), dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified via silica gel flash chromatography(eluting isocratically with 1% MeOH in CH₂Cl₂) to afford separately6-((5-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazoleand6-((4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazoleas white solids. The first eluting regioisomer is referred to asregioisomer 1 (55 mg, 16%) and the second eluting regioisomer isreferred to as regioisomer 2 (142 mg, 42%). The regiochemistry of thealkylation was examined by 2-dimensional nuclear Overhauser effect (NOE)experiment but was inconclusive. Regioisomer 1: ¹H NMR (300 MHz, CDCl₃)δ 7.81 (d, J=8.3 Hz, 1H), 7.60 (s, 1H), 7.37 (s, 1H), 7.31 (s, 1H), 7.19(s, 1H), 7.08-7.14 (m, 2H), 5.23 (s, 2H), 3.85 (s, 3H), 2.78 (s, 3H).LCMS (ESI) m/z 342 (M+H)⁺. Regioisomer 2: ¹H NMR (300 MHz, CDCl₃) δ 7.81(d, J=8.3 Hz, 1H), 7.60-7.71 (m, 2H), 7.47-7.56 (m, 2H), 7.22 (dd,J=1.6, 8.4 Hz, 1H), 6.94 (s, 1H), 5.15 (s, 2H), 3.87 (s, 3H), 2.76 (s,3H). LCMS (ESI) m/z 342 (M+H)⁺.

Step 5: To a stirred mixture of regioisomer 1 from Step 4 of thisExample (55 mg, 0.2 mmol) in CH₂Cl₂ (15 mL) at 0° C. was added 70-75%3-chloroperoxybenzoic acid (40 mg, 0.2 mmol). After the mixture wasstirred at 0° C. for 2 h, saturated aq NaHCO₃ (10 mL) was added. Themixture was stirred for 10 min and the CH₂Cl₂ layer was separated, driedover Na₂SO₄, filtered, and concentrated under reduced pressure to affordeither6-((5-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole or6-((4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (55 mg) as a white foam. The material was usedin the next step without further purification. LCMS (ESI) m/z 356(M+H)⁺.

Step 6: To a mixture of either6-((5-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole or6-((4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (55 mg, 0.2 mmol) from Step 5 of this Exampleand (1R,2R)-1-amino-2,3-dihydro-1H-inden-2-ol (48 mg, 0.4 mmol) NMP (1.5mL) was added DIEA (112 μL, 0.8 mmol). The reaction vessel was sealedand heated at 150° C. in the Biotage microwave reactor for 2 h. Themixture was directly purified by reverse-phase preparative HPLC using amixture of water (5% CH₃CN, 0.05% HCOOH) and CH₃CN (0.05% HCOOH) as themobile phase and Varian Pursuit XRs C18 column as the stationary phaseto afford a single compound identified as either(1R,2R)-1-((6-((4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-olor(1R,2R)-1-((6-((5-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol(alternative to Example 83) (6 mg, 7%) as a white powder. ¹H NMR (300MHz, DMSO-d₆) δ 8.47 (d, J=7.9 Hz, 1H), 7.72-7.86 (m, 2H), 7.49 (s, 1H),7.28-7.39 (m, 2H), 7.12-7.26 (m, 4H), 7.01 (s, 1H), 6.92 (dd, J=1.7, 8.3Hz, 1H), 5.52 (m, 1H), 5.28 (s, 2H), 5.17 (t, J=7.1 Hz, 1H), 4.30 (m,1H), 3.82 (s, 3H), 3.16 (m, 1H), 2.74 (m, 1H). LCMS (ESI) m/z 443(M+H)⁺.

Example 33 Preparation of(S)—N-(1-cyclohexylethyl)-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-amine

A stirred mixture of2-bromo-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazolefrom Example 2 (80 mg, 0.198 mmol), (S)-(+)-1-cyclohexylethylamine (50mg, 0.396 mmol) and DIEA (77 mg, 0.594 mmol) in anhydrous DMA (2 mL) washeated at 100° C. for 72 h. After cooling to rt, the mixture waspurified directly by reverse-phase HPLC using a mixture of water (5%CH₃CN, 0.05% HOAc) and CH₃CN (0.05% HOAc) as the mobile phase and VarianPursuit XRs diphenyl column as the stationary phase to afford(S)—N-(1-cyclohexylethyl)-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-amine(48 mg, 54%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.14 (s, 1H),7.89 (d, J=8.3 Hz, 1H), 7.62 (s, 1H), 7.29 (m, 1H), 7.12-7.23 (m, 3H),5.40 (s, 2H), 3.76 (2×s, 6H), 1.55-1.79 (m, 6H), 1.32 (m, 1H), 0.93-1.22(m, 8H). LCMS (ESI) m/z 451 (M+H)⁺.

Example 34 Preparation of(1R,2R)-2-((6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol

Step 1: To a stirred solution of(2-(methylthio)benzo[d]oxazol-6-yl)methanol (1.2 g, 6.15 mmol) fromExample 56 and DIEA (1.19 g, 9.23 mmol) in anhydrous DCM (40 mL) at 0°C. was added dropwise methanesulfonyl chloride (771 mg, 6.77 mmol). Themixture was allowed to warm to rt and was stirred for a further 2 h. Themixture was partitioned between saturated aq NaHCO₃ and DCM. The organiclayer was separated and washed with 2 M aq HCl. The organic layer wasseparated, dried over MgSO₄, filtered, and concentrated under reducedpressure to afford a 9:1 mixture of(2-(methylthio)benzo[d]oxazol-6-yl)methyl methanesulfonate and6-(chloromethyl)-2-(methylthio)benzo[d]oxazole (1.45 g) as a light pinksolid which was not purified further.(2-(Methylthio)benzo[d]oxazol-6-yl)methyl methanesulfonate: ¹H NMR (300MHz, DMSO-d₆) δ 7.78 (m, 1H), 7.68 (d, J=8.1 Hz, 1H), 7.45 (m, 1H), 5.36(s, 2H), 3.25 (s, 3H), 2.78 (s, 3H);6-(chloromethyl)-2-(methylthio)benzo[d]oxazole: ¹H NMR (300 MHz,DMSO-d₆) δ 7.75 (d, J=1.3 Hz, 1H), 7.63 (d, J=8.1 Hz, 1H), 7.43 (dd,J=1.3, 8.1 Hz, 1H), 4.89 (s, 2H), 2.77 (s, 3H).

Step 2: To a stirred solution of a 9:1 mixture of(2-(methylthio)benzo[d]oxazol-6-yl)methyl methanesulfonate and6-(chloromethyl)-2-(methylthio)benzo[d]oxazole (1.45 g) from Step 1 ofthis Example and 5,6-dimethoxybenzimidazole (945 mg, 5.31 mmol) inanhydrous DMF (10 mL) at rt was added solid K₂CO₃ (1.47 g, 10.62 mmol).The mixture was stirred at rt for 3 h. The mixture was partitionedbetween water and DCM. The organic layer was separated and washed withwater. The organic layer was separated, dried over MgSO₄, filtered, andconcentrated under reduced pressure. The residue was purified by silicagel flash chromatography eluting with 100% DCM to 10% MeOH in DCM toafford6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]oxazole(430 mg) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.20 (s, 1H), 7.66 (m,1H), 7.60 (d, J=9.0 Hz, 1H), 7.32 (dd, J=9.0, 3.0 Hz, 1H), 7.19 (s, 2H),5.53 (s, 2H), 3.76 (s, 6H), 2.73 (s, 3H). LCMS (ESI) m/z 356 (M+H)⁺.

Step 3: To a stirred solution of6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]oxazole(160 mg, 0.451 mmol) from Step 2 of this Example in DCM (2 mL) at 0° C.was added 70% meta-chloroperbenzoic acid (114 mg, 0.496 mmol) and themixture was allowed to warm to rt and stirred for a further 2.5 h. Tothe mixture was added saturated aq NaHCO₃ and the organic layer wasseparated. The aqueous layer was extracted with DCM and the combinedorganic layers were washed with saturated aq NaHCO₃. The organic layerwas separated, dried over MgSO₄, filtered, and concentrated underreduced pressure to afford a solid (121 mg). The solid was dissolved inanhydrous DMA (2 mL) and then (1R,2R)-(−)-2-aminocyclohexanol (38 mg,0.324 mmol) and DIEA (63 mg, 0.486 mmol) were added. The reaction vesselwas sealed and the mixture was heated at 90° C. for 15 h. After coolingto rt, the reaction mixture was purified directly by reverse-phase HPLCusing a mixture of water (5% CH₃CN, 0.05% HCOOH), CH₃CN (0.05% HCOOH) asthe mobile phase and Varian Pursuit XRs C-18 column as the stationaryphase to afford(1R,2R)-2-((6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol(35 mg) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.16 (s, 1H), 7.81(m, 1H), 7.35 (s, 1H), 7.11-7.21 (m, 4H), 5.41 (s, 2H), 4.70 (br s, 1H),3.76 (s, 6H), 1.80-2.00 (m, 2H), 1.55-1.67 (m, 2H), 1.15-1.30 (m, 4H).LCMS (ESI) m/z 423 (M+H)⁺.

Example 35 Preparation ofN-(cyclohexylmethyl)-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]oxazol-2-amine

Step 1: To a stirred solution of6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]oxazole(270 mg, 0.761 mmol) from Step 2 of Example 34 in DCM (5 mL) at 0° C.was added 70% meta-chloroperbenzoic acid (262 mg, 1.14 mmol), and themixture was allowed to warm to rt and stirred for a further 4.5 h. Tothe mixture was added saturated aq NaHCO₃ and the organic layer wasseparated. The aqueous layer was extracted with DCM and the combinedorganic layers were washed with saturated aq NaHCO₃. The organic layerwas separated, dried over MgSO₄, filtered, and concentrated underreduced pressure. The residue was purified via silica gel flashchromatography eluting with 100% DCM to 10% MeOH in DCM to afford6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole(127 mg, 45%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.24 (s, 1H),7.85-7.92 (m, 2H), 7.48 (d, J=8.3 Hz, 1H), 7.21 (s, 1H), 7.20 (s, 1H),5.62 (s, 2H), 3.76 (s, 6H), 3.18 (s, 3H). LCMS (ESI) m/z 372 (M+H)⁺.

Step 2: A stirred mixture of6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole (60 mg, 0.162 mmol), cyclohexylmethylamine (36mg, 0.323 mmol), and DIEA (63 mg, 0.485 mmol) in anhydrous DMA (2 mL)was heated at 90° C. for 15 h. After cooling to rt, the reaction mixturewas purified directly by reverse-phase HPLC using a mixture of water (5%CH₃CN, 0.05% HOAc), CH₃CN (0.05% HOAc) as the mobile phase and VarianPursuit XRs diphenyl column as the stationary phase to affordN-(cyclohexylmethyl)-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]oxazol-2-amine(20 mg) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.17 (s, 1H), 7.99(t, J=5.7 Hz, 1H), 7.37 (s, 1H), 7.11-7.24 (m, 4H), 5.42 (s, 2H), 3.77(s, 3H), 3.76 (s, 3H), 3.11 (t, J=6.2 Hz, 2H), 1.50-1.79 (m, 7H),1.07-1.26 (m, 2H), 0.81-1.00 (m, 2H). LCMS (ESI) m/z 421 (M+H)⁺.

Example 36 Preparation of(1R,2R)-2-((6-((4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: To a stirred mixture of CuBr₂ (6.5 g, 0.03 mol) andt-butylnitrite (3.9 g, 0.04 mol) in CH₃CN (100 mL) at 0° C. under argonwas added ethyl 2-aminobenzo[d]thiazole-6-carboxylate (5.0 g, 0.02 mol)portionwise. After stirring at 0° C. for 15 min, the mixture was allowedto warm to rt and stirred under argon for 2 h. 2 N HCl (300 ml) wasadded and the resulting solution was extracted with EtOAc (2×200 mL).The combined EtOAc layers were washed with brine (100 mL), dried overMgSO₄, filtered, and concentrated under reduced pressure. The residuewas purified by silica gel flash chromatography eluting with a gradientof 100% hexanes to 50% EtOAc in hexanes to afford ethyl2-bromobenzo[d]thiazole-6-carboxylate (3.94 g, 61%) as a yellow solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.05-8.12 (m, 2H), 4.37 (q,J=7.2 Hz, 2H), 1.36 (t, J=7.1 Hz, 3H). LCMS (ESI) m/z 286 and 288(M+H)⁺.

Step 2: To a stirred mixture of 2-bromobenzo[d]thiazole-6-carboxylate(2.3 g, 7.9 mmol) from Step 1 of this Example in THF (15 mL) at 0° C.was added sodium thiomethoxide (607 mg, 8.7 mmol) in one portion. Themixture was allowed to warm to rt and stirred for 20 h. The mixture waspartitioned between EtOAc (150 mL) and water (100 mL). The EtOAc layerwas separated and washed with water (100 mL) and brine (100 mL), driedover MgSO₄, filtered, and concentrated under reduced pressure to affordethyl 2-(methylthio)benzo[d]thiazole-6-carboxylate (1.7 g, 83%) as ayellow solid which did not require further purification. ¹H NMR (300MHz, DMSO-d₆) δ 8.69 (d, J=1.3 Hz, 1H), 8.02 (m, 1H), 7.92 (m, 1H), 4.35(q, J=7.0 Hz, 2H), 2.83 (s, 3H), 1.35 (t, J=7.1 Hz, 3H). LCMS (ESI) m/z254 (M+H)⁺.

Step 3: To a stirred mixture of ethyl2-(methylthio)benzo[d]thiazole-6-carboxylate (1.7 g, 6.6 mmol) from Step2 of this Example in CH₂Cl₂ (50 mL) at −78° C. under argon was added 1 Mdiisobutyl aluminum hydride in CH₂Cl₂ (13.8 mL, 13.8 mmol) dropwise.After the mixture was stirred at −78° C. under argon for 3 h, it wasallowed to warm slowly to 0° C. To the stirring mixture was added asaturated aq potassium sodium tartrate (50 mL) and the mixture wasallowed to slowly warm to rt. After the mixture was stirred for 12 h,the organic layer was separated, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by silicagel flash chromatography eluting with a gradient of 100% hexanes to 100%EtOAc to afford (2-(methylthio)benzo[d]thiazol-6-yl)methanol (1.05 g,76%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.93 (m, 1H), 7.79(d, J=8.3 Hz, 1H), 7.40 (dd, J=1.3, 8.3 Hz, 1H), 5.32 (t, J=5.7 Hz, 1H),4.60 (d, J=5.8 Hz, 2H), 2.78 (s, 3H). LCMS (ESI) m/z 212 (M+H)⁺.

Step 4: To a stirred mixture of(2-(methylthio)benzo[d]thiazol-6-yl)methanol (1.05 g, 5 mmol) from Step3 of this Example and DIEA (1.3 mL, 7.5 mmol) in anhydrous CH₂Cl₂ (20mL) under argon at −10° C. was added dropwise a solution ofmethanesulfonyl chloride (0.6 g, 5.5 mmol) in CH₂Cl₂ (10 mL). Themixture was allowed to warm to rt and stirred for 3 h. Additionalmethanesulfonyl chloride (190 mg, 1.7 mmol) was added, and the mixturewas stirred for a further 2 h. Water (50 mL) was added, and the mixturewas stirred for 10 min. The resulting mixture was then extracted withCH₂Cl₂ (200 mL). The CH₂Cl₂ layer was separated, dried over Na₂SO₄,filtered, and concentrated under reduced pressure to afford6-(chloromethyl)-2-(methylthio)benzo[d]thiazole (1.0 g, 88%) as a lightred solid. The material was used in the next step without furtherpurification. LCMS (ESI) m/z 230 (M+H)⁺.

Step 5: To a stirred mixture of6-(chloromethyl)-2-(methylthio)benzo[d]thiazole (0.2 g, 0.9 mmol) fromStep 4 of this Example and 4-bromo-1H-imidazole (0.2 g, 1.3 mmol) inanhydrous DMF (3.0 mL) was added K₂CO₃ (0.37 g, 2.7 mmol). After stirredfor 3 h at rt, the reaction mixture was partitioned between EtOAc (100mL) and water (50 mL). The EtOAc layer was separated, washed with brine(50 ml), dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by silica gel flash chromatographyeluting with a gradient of 30% EtOAc in hexanes to 100% EtOAc to afford6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (160mg, 54%) as a yellow oil. The regiochemistry of the alkylation wasdetermined by 2-dimensional nuclear Overhauser effect (NOE) experiment.¹H NMR (300 MHz, CDCl₃) δ 7.85 (d, J=8.3 Hz, 1H), 7.54 (d, J=1.1 Hz,1H), 7.45 (d, J=1.3 Hz, 1H), 7.24 (dd, J=1.7, 8.5 Hz, 1H), 6.88 (d,J=1.5 Hz, 1H), 5.17 (s, 2H), 2.80 (s, 3H). LCMS (ESI) m/z 340 and 342(M+H)⁺.

Step 6: To a stirred mixture of6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (105mg, 0.3 mmol) from Step 5 of this Example in CH₂Cl₂ (15 mL) at 0° C. wasadded 70-75% 3-chloroperoxybenzoic acid (91 mg, 0.4 mmol). After themixture was stirred at 0° C. for 2 h, saturated aq NaHCO₃ (10 mL) wasadded. The mixture was stirred for 10 min and the CH₂Cl₂ layer wasseparated, dried over Na₂SO₄, filtered, and concentrated under reducedpressure to afford6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole(130 mg) as a white foam. The material was used in the next step withoutfurther purification. LCMS (ESI) m/z 356 and 358 (M+H)⁺.

Step 7: To a suspension of6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole(130 mg, 0.37 mmol) from Step 6 of this Example and(1R,2R)-2-aminocyclohexanol (126 mg, 1 mmol) in anhydrous DMA (1.0 mL)was added DIEA (320 μL, 1.8 mmol). The mixture was heated in a sealedtube at 110° C. for 7 h. The mixture was cooled to rt and water wasslowly added while stirring to give a precipitate. The mixture stirredfor 10 min and the solid was collected by filtration to afford(1R,2R)-2-((6-((4-bromo-1H-imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(100 mg, 68%) as a tan solid. The material was used in the next stepwithout further purification. LCMS (ESI) m/z 407 and 409 (M+H)⁺.

Step 8: To a suspension of(1R,2R)-2-((6-((4-bromo-1H-imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(50 mg, 0.12 mmol) from Step 7 of this Example and1-methylpyrazole-4-boronic acid pinacol ester (51 mg, 0.25 mmol) in amixture of DME (0.7 mL) and H₂O (0.3 mL) was added K₂CO₃ (68 mg, 0.5mmol). Argon was bubbled into the mixture for 5 min. To the mixture wasadded tetrakis(triphenylphosphine)palladium (0) (14 mg, 0.01 mmol).Argon was bubbled into the mixture for 5 min. The reaction vessel wassealed and the mixture was heated at 100° C. for 16 h. Additionalportions of 1-methylpyrazole-4-boronic acid pinacol ester (51 mg, 0.25mmol) and tetrakis(triphenylphosphine)palladium (0) (14 mg, 0.01 mmol)were added to the mixture and argon was bubbled into the mixture for 5min. The reaction vessel was sealed and the mixture was heated at 110°C. for 4 h. The mixture was cooled to rt and partitioned between EtOAc(100 mL) and aq 1 N K₂CO₃ (50 mL). The EtOAc layer was separated andwashed with water (50 mL) and brine (50 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by preparative reverse-phase HPLC using a mixture of water (5%CH₃CN, 0.05% HCOOH) and CH₃CN (0.05% HCOOH) as the mobile phase andVarian Pursuit XRs C18 column as the stationary phase to afford(1R,2R)-2-((6-((4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(10.3 mg, 20%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.97 (d,J=7.5 Hz, 1H), 7.80 (s, 1H), 7.71 (s, 1H), 7.54-7.62 (m, 2H), 7.32 (d,J=8.3 Hz, 1H), 7.24 (s, 1H), 7.16 (dd, J=1.3, 8.3 Hz, 1H), 5.13 (s, 2H),4.75 (brm, 1H), 3.80 (s, 3H), 3.52 (br s, 1H), 3.34 (br s, 1H), 2.04 (d,J=10.2 Hz, 1H), 1.88 (d, J=9.4 Hz, 1H), 1.55-1.66 (m, 2H), 1.10-1.33 (m,4H). LCMS (ESI) m/z 409 (M+H)⁺.

Example 37 Preparation of1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-N-methyl-1H-imidazole-4-carboxamide

Step 1: To a stirred mixture of6-(chloromethyl)-2-(methylthio)benzo[d]thiazole (500 mg, 2.2 mmol) fromExample 36 and methyl 4-imidazole carboxylate (400 mg, 3.3 mmol) in DMF(15 mL) was added K₂CO₃ (0.9 g, 6.5 mmol). After the mixture was stirredfor 3 h at rt, it was partitioned between EtOAc (100 mL) and water (50mL). The EtOAc layer was separated and washed with water (50 mL) andbrine (50 mL), then dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by silica gel flashchromatography eluting with 2% MeOH in CH₂Cl₂ to afford methyl1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-1H-imidazole-4-carboxylate(130 mg, 19%) as a white solid. The regiochemistry of the alkylation wasdetermined by 2-dimensional nuclear Overhauser effect (NOE) experiment.¹H NMR (300 MHz, DMSO-d₆) δ 8.01 (d, J=0.9 Hz, 1H), 7.98 (d, J=1.1 Hz,1H), 7.93 (d, J=0.9 Hz, 1H), 7.84 (d, J=8.3 Hz, 1H), 7.43 (dd, J=1.7,8.3 Hz, 1H), 5.35 (s, 2H), 3.72 (s, 3H), 2.78 (s, 3H). LCMS (ESI) m/z322 (M+H)⁺.

Step 2: To a stirred solution of methylamine (623 μL of a 2 M solutionin THF, 1.3 mmol) at 0° C. was added trimethylaluminum (623 μL of a 2 Msolution in toluene, 1.2 mmol). The mixture was stirred for 2 min andthen a solution of1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-1H-imidazole-4-carboxylate(80 mg, 0.25 mmol) from Step 1 of this Example in DCE (1 mL) was addeddropwise. The reaction vessel was sealed and the mixture was heated at70° C. for 20 h. The mixture was then concentrated under reducedpressure and the residue was purified by silica gel flash chromatographyeluting with 5% MeOH in EtOAc to affordN-methyl-1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-1H-imidazole-4-carboxamide(46 mg, 58%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.98 (d,J=1.3 Hz, 1H), 7.81-7.94 (m, 3H), 7.71 (d, J=1.1 Hz, 1H), 7.42 (dd,J=1.6, 8.4 Hz, 1H), 5.33 (s, 2H), 2.78 (s, 3H), 2.70 (d, J=4.9 Hz, 3H).LCMS (ESI) m/z 319 (M+H)⁺.

Step 3:N-Methyl-1-((2-(methylsulfinyl)benzo[d]thiazol-6-yl)methyl)-1H-imidazole-4-carboxamidewas synthesized as a white foam (76 mg, 100%) using a procedureanalogous to that described in Step 6 of Example 36, substitutingN-methyl-1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-1H-imidazole-4-carboxamidefrom Step 2 of this Example for6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole usedin Example 36. LCMS (ESI) m/z 335 (M+H)⁺.

Step 4:1-((2-(((1R,2R)-2-Hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-N-methyl-1H-imidazole-4-carboxamidewas synthesized as a white powder (26 mg, 46%) using a procedureanalogous to that described in Step 7 of Example 36, substitutingN-methyl-1-((2-(methylsulfinyl)benzo[d]thiazol-6-yl)methyl)-1H-imidazole-4-carboxamide fromStep 3 of this Example for6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methyl sulfinyl)benzo[d]thiazoleused in Example 36 and subjecting the crude residue to purification byreverse-phase preparative HPLC using a mixture of water (5% CH₃CN, 0.05%HCOOH) and CH₃CN (0.05% HCOOH) as the mobile phase and Varian PursuitXRs C18 column as the stationary phase. ¹H NMR (300 MHz, DMSO-d₆) δ 8.01(d, J=7.5 Hz, 1H), 7.84-7.92 (m, 1H), 7.80 (d, J=1.1 Hz, 1H), 7.62-7.67(m, 2H), 7.31 (d, 1H), 7.18 (dd, J=1.7, 8.3 Hz, 1H), 5.18 (s, 2H), 4.77(br m, 1H), 3.55 (br m, 1H), 3.35 (br m, 1H), 2.69 (br m, 3H), 2.04 (brm 1H), 1.86 (br m, 1H), 1.61 (br m, 2H), 1.10-1.35 (br m, 4H). LCMS(ESI) m/z 386 (M+H)⁺.

Example 38 Preparation of(1R,2R)-2-((6-(imidazo[1,2-a]pyridin-3-ylmethyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: A stirred mixture of 2-fluoro-4-iodoaniline (5.0 g, 21.1 mmol),CuI (90 mg, 0.42 mmol), and PdCl₂(PPh₃)₂(300 mg, 0.42 mmol) in apressure tube was flushed with argon. Ethynyltrimethylsilane (2.28 g,23.2 mmol) in TEA (20 mL) was added and the resulting mixture wasstirred at rt over night. The reaction mixture was then diluted withEt₂O and filtered through a Celite pad. The filtrate was concentratedunder reduced pressure and the residue was purified by silica gelchromatography eluting with 5% EtOAc in hexanes to afford2-fluoro-4-((trimethylsilyl)ethynyl)aniline (4.4 g, 100%) as a brownsolid. LCMS (ESI) m/z 208 (M+H)⁺.

Step 2: To a solution of 2-fluoro-4-((trimethylsilyl)ethynyl)aniline(4.4 g, 21.2 mmol) from Step 1 of this Example in 20 mL of DMF was addedpotassium O-ethyl carbonodithioate (7.48 g, 46.8 mmol). The resultingmixture was heated under reflux for 4 h. After cooling to rt, thereaction mixture was treated with water (30 mL) and 1N HCl (100 mL). Themixture was stirred at rt for 2 h before the precipitates were collectedby filtration and washed with water to give the crude6-ethynylbenzo[d]thiazole-2-thiol (4.0 g, 99%) as a dark brown solid.LCMS (ESI) m/z 192 (M+H)⁺.

Step 3: To a stirred solution of 6-ethynylbenzo[d]thiazole-2-thiol (4.0g, 21 mmol) from Step 2 of this Example in 20 mL of DMF at 0° C. wereadded K₂CO₃ (7.25 g, 5.25 mmol), and MeI (5 mL). The mixture was stirredat rt for 2 h before it was partitioned between EtOAc and water, theorganic layer was washed with brine, dried over Na₂SO₄, and concentratedunder reduced pressure. The residue was purified by silica gelchromatography eluting with 3:1 DCM/hexanes to afford6-ethynyl-2-(methylthio)benzo[d]thiazole (1.5 g, 35%) as an off-whitesolid. LCMS (ESI) m/z 206 (M+H)⁺.

Step 4: A stirred mixture of 2-aminopyridine (100 mg, 1.1 mmol),paraformaldehyde (34 mg, 1.1 mmol), CuCl (5 mg, 0.06 mmol), and Cu(OTf)₂(19 mg, 0.06 mmol) in 3 mL of toluene in a pressure tube was flushedwith argon. 6-Ethynyl-2-(methylthio)benzo[d]thiazole (327 mg, 1.6 mmol)from Step 3 of this Example was added. The reaction vessel was sealedand the mixture was heated in an oil bath at 120° C. for 6 h. LCMSanalysis showed that the reaction was mostly complete. The reactionmixture was partitioned between EtOAc and saturated aq NaHCO₃. Theorganic layer was washed with brine, dried over Na₂SO₄, and concentratedunder reduced pressure. The residue was purified by silica gelchromatography eluting with 0-100% EtOAc in hexanes to afford6-(imidazo[1,2-a]pyridin-3-ylmethyl)-2-(methylthio)benzo[d]thiazole (127mg, 38%) as a brown oil. LCMS (ESI) m/z 312 (M+H)⁺.

Step 5:(1R,2R)-2-((6-(Imidazo[1,2-a]pyridin-3-ylmethyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(28 mg, 18%) was obtained as a yellow powder using procedures analogousto those described in Step 5 of Example 3 and Step 5 of Example 2,sequentially, substituting6-(imidazo[1,2-a]pyridin-3-ylmethyl)-2-(methylthio)benzo[d]thiazole fromStep 4 of this Example for6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazoleused in Example 3. ¹H NMR (300 MHz, DMSO-d₆) δ 8.20 (d, J=6.4 Hz, 1H),7.89 (d, J=7.5 Hz, 1H), 7.48-7.62 (m, 2H), 7.43 (br s, 1H), 7.27 (d,J=8.1 Hz, 1H), 7.14-7.23 (m, 1H), 7.09 (dd, J=1.2, 8.2 Hz, 1H), 6.86 (t,J=6.7 Hz, 1H), 4.75 (br s, 1H), 4.29 (s, 2H), 3.47-3.59 (m, 1H), 2.03(d, J=10.4 Hz, 1H), 1.88 (br s, 2H), 1.61 (br s, 2H), 1.23 (d, J=5.5 Hz,4H). LCMS (ESI) m/z 379 (M+H)⁺.

Example 39 Preparation of(1R,2R)-2-((6-((6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

A stirred mixture of(1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolfrom Example 29(80 mg, 0.175 mmol), 1-methylpyrazole-4-boronic acidpinacol ester (73 mg, 0.351 mmol), 2M aq Na₂CO₃ (400 μL, 0.40 mmol), andanhydrous DME (1.5 mL) was degassed under argon for 15 min.Bis(triphenylphosphine)palladium (II) dichloride (12 mg, 0.0171 mmol)was added and the reaction vessel was sealed and the mixture was heatedat 100° C. for 15 h. After cooling to rt, the mixture was purifieddirectly by reverse-phase HPLC using a mixture of water (5% CH₃CN, 0.05%HOAc) and CH₃CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRsdiphenyl column as the stationary phase to afford(1R,2R)-2-((6-((6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(33 mg, 41%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.64 (d,J=1.9 Hz, 1H), 8.56 (s, 1H), 8.26 (d, J=1.9 Hz, 1H), 8.23 (s, 1H),7.95-8.01 (m, 2H), 7.67 (d, J=1.1 Hz, 1H), 7.20-7.32 (m, 2H), 5.47 (s,2H), 4.76 (br s, 1H), 3.88 (s, 3H), 3.51 (m, 1H), 3.35 (m, 1H), 2.03 (m,1H), 1.90 (m, 1H), 1.62 (d, J=4.7 Hz, 2H), 1.10-1.33 (m, 4H). LCMS (ESI)m/z 460 (M+H)⁺.

Example 40 Preparation of(1R,2R)-2-((6-((6-(pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

A stirred mixture of(1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(80 mg, 0.175 mmol) from Example 29, pyridine-3-ylboronic acid (43 mg,0.350 mmol), 2M aq Na₂CO₃ (400 μL, 0.40 mmol), and anhydrous DME (1.5mL) was degassed under argon for 15 min.Bis(triphenylphosphine)palladium (II) dichloride (12 mg, 0.0171 mmol)was added and the reaction vessel was sealed and the mixture was heatedat 100° C. for 15 h. After cooling to rt, the mixture was purifieddirectly by reverse-phase HPLC using a mixture of water (5% CH₃CN, 0.05%HOAc) and CH₃CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRsdiphenyl column as the stationary phase to afford(1R,2R)-2-((6-((6-(pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(25 mg, 31%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.99 (br s,1H), 8.66-8.77 (m, 2H), 8.60 (br s, 1H), 8.46 (s, 1H), 8.19 (d, J=7.9Hz, 1H), 8.00 (d, J=7.3 Hz, 1H), 7.69 (s, 1H), 7.52 (dd, J=4.7, 7.7 Hz,1H), 7.21-7.34 (m, 2H), 5.53 (s, 2H), 4.77 (br s, 1H), 3.51 (m, 1H),3.35 (m, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.56-1.66 (m, 2H), 1.11-1.34(m, 4H). LCMS (ESI) m/z 457 (M+H)⁺.

Example 41 Preparation of(1R,2R)-2-((6-((5-bromo-6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: To a stirred mixture of DMF (15 mL) and NaH (60% in mineral oil,75 mg, 1.9 mmol) at −10° C. under argon was added4-bromo-5-methoxy-2-nitroaniline (490 mg, 2.2 mmol) in one portion. Themixture was stirred for 5 min at −10° C. A solution of6-(chloromethyl)-2-(methylthio)benzo[d]thiazole from Example 36 (500 mg,2.2 mmol) in DMF (5 mL) was added dropwise. After stirring at −10° C.for 1 h, the mixture was allowed to warm slowly to rt. The mixture wasstirred at rt for 58 h and then partitioned between EtOAc (150 mL) and 1M aq Na₂CO₃ (50 mL). The EtOAc layer was separated and washed with water(50 mL) and brine, dried over Na₂SO₄, filtered, and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel flash chromatography eluting with a gradient of 100% hexanes to 100%EtOAc to afford4-bromo-5-methoxy-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroaniline(239 mg, 25%) as an orange solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.02 (t,J=5.8 Hz, 1H), 8.23 (s, 1H), 8.06 (s, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.53(d, J=8.3 Hz, 1H), 6.40 (s, 1H), 4.80 (d, J=5.8 Hz, 2H), 3.77 (s, 3H),2.78 (s, 3H). LCMS (ESI) m/z 440 and 442 (M+H)⁺.

Step 2: To a stirred suspension of4-bromo-5-methoxy-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroaniline(212 mg, 0.5 mmol) from Step 1 of this Example in EtOH (4 mL) and HOAc(2 mL) at 0° C. under argon was added zinc powder (160 mg, 2.4 mmol) inone portion. After 1.5 h at 0° C., MeOH (5 mL), additional HOAc (2 mL),and zinc powder (160 mg, 2.4 mmol) were added. The mixture was allowedto warm to rt and stirred for 18 h. The mixture was filtered and thefiltrate was cooled to 0° C. The pH of the filtrate was adjusted to pH˜9by addition of solid Na₂CO₃. The mixture was then partitioned betweenEtOAc (150 mL) and water (100 mL). The EtOAc layer was separated, driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by silica gel flash chromatography eluting with agradient of 100% hexanes to 100% EtOAc to afford4-bromo-5-methoxy-N1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine(120 mg, 61%). LCMS (ESI) m/z 410 and 412 (M+H)⁺.

Step 3: To a stirred mixture of4-bromo-5-methoxy-N¹-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine(120 mg, 0.3 mmol) from Step 2 of this Example and triethylorthoformate(20 mL) was added formic acid (1 mL). The mixture was heated underreflux for 2 h, then concentrated under reduced pressure. The residuewas purified by silica gel flash chromatography eluting with 100% EtOActo afford6-((5-bromo-6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole(50 mg, 40%) as an oil. ¹H NMR (300 MHz, CDCl₃) δ 8.01 (s, 1H),7.78-7.91 (m, 2H), 7.46 (s, 1H), 7.25 (m, 1H), 6.69 (s, 1H), 5.42 (s,2H), 3.81 (s, 3H), 2.78 (s, 3H). LCMS (ESI) m/z 420 and 422 (M+H)⁺.

Step 4:6-((5-Bromo-6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazolewas synthesized as a white foam (75 mg) using a procedure analogous tothat described in Step 6 of Example 36, substituting6-((5-bromo-6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazolefrom Step 3 of this Example for6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole usedin Example 36. LCMS (ESI) m/z 436 and 438 (M+H)⁺.

Step 5:(1R,2R)-2-((6-((5-Bromo-6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolwas synthesized as a white powder (15 mg, 26%) using a procedureanalogous to that described in Step 4 of Example 37, substituting6-((5-bromo-6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazolefrom Step 4 of this Example forN-methyl-1-((2-(methylsulfinyl)benzo[d]thiazol-6-yl)methyl)-1H-imidazole-4-carboxamideused in Example 37. ¹H NMR (300 MHz, DMSO-d₆) δ 8.29 (s, 1H), 7.98 (d,J=7.5 Hz, 1H), 7.85 (s, 1H), 7.66 (d, J=1.1 Hz, 1H), 7.37 (s, 1H),7.27-7.33 (m, 1H), 7.22 (dd, J=9, 1.5 Hz, 1H), 5.46 (s, 2H), 4.75 (d,J=4.9 Hz, 1H), 3.85 (s, 3H), 3.52 (br m, 1H), 3.33 (br m, 1H), 2.02 (brm, 1H), 1.85 (br m, 1H), 1.55-1.68 (br m, 2H), 1.10-1.34 (br m, 4H).LCMS (ESI) m/z 487 and 489 (M+H)⁺.

Example 42 Preparation of(1R,2R)-1-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol

A stirred mixture of6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazolefrom Example 29 (210 mg, 0.3 mmol),(1R,2R)-1-amino-2,3-dihydro-1H-inden-2-ol (92 mg, 0.6 mmol), and DIEA(267 μL, 1.5 mmol) in DMA (3 mL) was heated at 130° C. for 120 h in asealed tube. The mixture was cooled to rt and subjected to purificationby reverse-phase preparative HPLC using a mixture of water (5% CH₃CN,0.05% HCOOH) and CH₃CN (0.05% HCOOH) as the mobile phase and VarianPursuit XRs C18 column as the stationary phase to afford(1R,2R)-1-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol(5.4 mg, 4%) as a white powder. ¹H NMR (300 MHz, DMSO-d₆) δ 8.68 (s,1H), 8.36-8.54 (m, 3H), 7.71 (s, 1H), 7.35 (m, 1H), 7.11-7.30 (m, 5H),5.51 (s, 2H), 5.18 (t, J=7.0 Hz, 1H), 4.30 (m, 1H), 3.16 (dd, J=7.2,15.8 Hz, 1H), 2.74 (dd, J=7.3, 15.4 Hz, 1H). LCMS (ESI) m/z 492 and 494(M+H)⁺.

Example 43 Preparation of3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile

A stirred mixture of(1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolfrom Example 29 (170 mg, 0.372 mmol), zinc cyanide (131 mg, 1.12 mmol),1,1′-bis(diphenylphosphino)ferrocene (31 mg, 0.0558 mmol) and anhydrousDMF (2 mL) was degassed under argon for 15 min.Tris(dibenzylideneacetone) dipalladium (0) (34 mg, 0.0372 mmol) wasadded. The reaction vessel was sealed and the mixture was heated at 100°C. for 6 h. After cooling to rt, the mixture was purified directly byreverse-phase HPLC using a mixture of water (5% CH₃CN, 0.05% HCOOH) andCH₃CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18column as the stationary phase to afford((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile(51 mg, 34%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.80-8.91 (m,2H), 8.72 (d, J=1.5 Hz, 1H), 7.99 (d, J=7.3 Hz, 1H), 7.68 (s, 1H),7.20-7.34 (m, 2H), 5.53 (s, 2H), 4.74 (br s, 1H), 3.29-3.38 (m, 2H),2.04 (m, 1H), 1.88 (m, 1H), 1.55-1.70 (m, 2H), 1.10-1.35 (m, 4H). LCMS(ESI) m/z 405 (M+H)⁺.

Example 44 Preparation of(1R,2R)-2-((6-((7-methoxyimidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

(1R,2R)-2-((6-((7-Methoxyimidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(25 mg) was obtained as a yellow powder using procedures analogous tothose described in Steps 4-5 of Example 38, substituting4-methoxypyridin-2-amine for 2-aminopyridine used in Example 38. ¹H NMR(300 MHz, DMSO-d₆) δ 8.03 (d, J=7.3 Hz, 1H), 7.87 (d, J=7.5 Hz, 1H),7.49 (s, 1H), 7.17-7.33 (m, 2H), 7.07 (dd, J=1.2, 8.2 Hz, 1H), 6.92 (d,J=2.3 Hz, 1H), 6.59 (dd, J=2.4, 7.4 Hz, 1H), 4.73 (br s, 1H), 4.22 (s,2H), 3.80 (s, 3H), 3.41-3.63 (m, 2H), 2.03 (d, J=10.2 Hz, 1H), 1.88 (d,J=9.6 Hz, 1H), 1.61 (br s, 2H), 1.23 (d, J=5.3 Hz, 4H). LCMS (ESI) m/z409 (M+H)⁺.

Example 45 Preparation of(1R,2R)-2-((6-((6-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

A stirred mixture of(1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolfrom Example 29 (30 mg, 0.0656 mmol), cyclopropylboronic acid (11 mg,0.131 mmol), K₂CO₃ (36 mg, 0.262 mmol),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (16 mg, 0.0328mmol) and anhydrous toluene (1 mL) was degassed under argon for 15 min.Tris(dibenzylideneacetone) dipalladium (0) (6 mg, 0.0066 mmol) wasadded. The reaction vessel was sealed and the mixture was heated at 100°C. for 15 h. After cooling to rt, the mixture was purified directly byreverse-phase HPLC using a mixture of water (5% CH₃CN, 0.05% HOAc) andCH₃CN (0.05% HOAc) as the mobile phase and Phenomenex Luna C-18 columnas the stationary phase to afford(1R,2R)-2-((6-((6-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(1 mg, 4%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.51 (s, 1H),8.24 (d, J=1.5 Hz, 1H), 8.03 (d, J=7.3 Hz, 1H), 7.70 (d, J=1.5 Hz, 1H),7.63 (s, 1H), 7.28 (m, 1H), 7.19 (m, 1H), 5.44 (s, 2H), 4.82 (br s, 1H),1.97-2.13 (m, 2H), 1.85 (m, 1H), 1.54-1.74 (m, 3H), 1.09-1.34 (m, 4H),0.92-1.02 (m, 2H), 0.70-0.80 (m, 2H). LCMS (ESI) m/z 420 (M+H)⁺.

Example 46 Preparation of(1R,2R)-1-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol

(1R,2R)-1-((6-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-olwas synthesized as a white powder (8 mg, 6%) using a procedure analogousto that described in Example 42, substituting6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazolefrom Example 3 for6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazoleused in Example 42. ¹H NMR (300 MHz, DMSO-d₆) δ 8.62 (s, 1H), 8.46 (d,J=8.1 Hz, 1H), 8.39 (dd, J=1.3, 4.7 Hz, 1H), 8.10 (dd, J=1.3, 8.1 Hz,1H), 7.73 (d, J=1.1 Hz, 1H), 7.10-7.40 (m, 7H), 5.51 (s, 2H), 5.17 (t,J=7.2 Hz, 1H), 4.29 (m, 1H), 3.16 (dd, J=7.0, 15.6 Hz, 1H), 2.74 (m,1H). LCMS (ESI) m/z 414 (M+H)⁺.

Example 47 Preparation of(1R,2R)-2-((6-((6-bromo-5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: To a stirred mixture of 4-bromo-5-methoxy-2-nitroaniline (5 g,20 mmol) in MeOH (50 mL) and HOAc (20 mL) at 0° C. under argon was addedzinc powder (5.3 g, 80 mmol) portionwise. The mixture was stirred for 2h, then filtered, and the filtrate was cooled to 0° C. The pH of thefiltrate was adjusted to pH˜9 by addition of solid Na₂CO₃. The mixturewas then partitioned between EtOAc (250 mL) and water (200 mL). TheEtOAc layer was separated, dried over Na₂SO₄, filtered, and concentratedunder reduced pressure to afford 4-bromo-5-methoxybenzene-1,2-diamine(3.8 g, 88%) as a dark purple solid. The material was used in the nextstep without further purification. ¹H NMR (300 MHz, DMSO-d₆) δ 6.66 (s,1H), 6.34 (s, 1H), 4.08-4.83 (m, 4H), 3.63 (s, 3H). LCMS (ESI) m/z 217and 219 (M+H)⁺.

Step 2: To a stirred mixture of 4-bromo-5-methoxybenzene-1,2-diamine(3.8 g, 18 mmol) from Step 1 of this Example and triethyl orthoformate(50 mL) was added formic acid (1 mL). The mixture was heated at refluxfor 3 h, then concentrated under reduced pressure. The residue waspartitioned between EtOAc (200 mL) and a 1 N aq Na₂CO₃ (100 mL). TheEtOAc layer was separated, washed with brine (100 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure to afford5-bromo-6-methoxy-1H-benzo[d]imidazole (4.0 g) as a brown oil. Thematerial was used in the next step without further purification. LCMS(ESI) m/z 228 and 230 (M+H)⁺.

Step 3: To a stirred mixture of DMF (3 mL) and NaH (60% in mineral oil,67 mg, 1.6 mmol) at 0° C. under argon was added5-bromo-6-methoxy-1H-benzo[d]imidazole (346 mg, 1.5 mmol) from Step 2 ofthis Example in one portion. The mixture was stirred for 5 min at 0° C.A solution of 6-(chloromethyl)-2-(methylthio)benzo[d]thiazole (500 mg,2.2 mmol) from Step 4 of Example 36 in DMF (3 mL) was added dropwise.The mixture was stirred at 0° C. for 1 h, then allowed to warm slowly tort and stirred for 6 h. The mixture was then partitioned between EtOAc(100 mL) and water (50 mL). The EtOAc layer was separated and washedwith brine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by silica gel flash chromatographyeluting with 100% EtOAc to afford the two regioisomers: Regioisomer 1;6-((5-bromo-6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole(127 mg, 20%). The structure was confirmed by comparison with NMR fromthe regiospecific synthesis of the same compound described in Step 3 ofExample 41. ¹H NMR (300 MHz, CDCl₃) δ 8.02 (s, 1H), 7.78-7.91 (m, 2H),7.47 (s, 1H), 7.25 (m, 1H), 6.70 (s, 1H), 5.43 (s, 2H), 3.82 (s, 3H),2.79 (s, 3H). LCMS (ESI) m/z 420 and 422 (M+H)⁺. Regioisomer 2;6-((6-bromo-5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole(81 mg, 13%). ¹H NMR (300 MHz, CDCl₃) δ 7.92 (s, 1H), 7.84 (d, J=8.5 Hz,1H), 7.48 (m, 2H), 7.34 (s, 1H), 7.25 (m, 1H), 5.40 (s, 2H), 3.94 (s,3H), 2.79 (s, 3H). LCMS (ESI) m/z 420 and 422 (M+H)⁺.

Step 4:6-((6-Bromo-5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazolewas synthesized as a white foam (115 mg) using a procedure analogous tothat described in Step 6 of Example 36, substituting6-((6-bromo-5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole(regioisomer 2 from Step 3 of this Example) for6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole usedin Example 36. LCMS (ESI) m/z 436 and 438 (M+H)⁺.

Step 5:(1R,2R)-2-((6-((6-Bromo-5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolwas synthesized as a white powder (15 mg, 19%) using a procedureanalogous to that described in Step 4 of Example 37, substituting6-((5-bromo-5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazolefrom Step 4 of this Example forN-methyl-1-((2-(methylsulfinyl)benzo[d]thiazol-6-yl)methyl)-1H-imidazole-4-carboxamideused in Example 37. ¹H NMR (300 MHz, DMSO-d₆) δ 8.37 (s, 1H), 7.98 (d,J=7.5 Hz, 1H), 7.79-7.91 (m, 2H), 7.63 (s, 1H), 7.35 (s, 1H), 7.17 (dd,J=1.6, 8.2 Hz, 1H), 5.43 (s, 2H), 4.75 (br s, 1H), 3.84 (s, 3H), 3.51(m, 1H), 3.33 (m, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.13-1.35 (br m, 2H),1.09-1.35 (m, 4H). LCMS (ESI) m/z 487 and 489 (M+H)⁺.

Example 48 Preparation of(1R,2R)-2-((6-((9H-purin-9-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: 2-(Methylsulfinyl)benzo[d]thiazole-6-carbonitrile wassynthesized as a tan solid (6.0 g) using a procedure analogous to thatdescribed in Step 5 of Example 3, substituting2-(methylthio)benzo[d]thiazole-6-carbonitrile from Step 3 of Example 23for6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazoleused in Example 3. LCMS (ESI) m/z 223 (M+H)⁺.

Step 2:2-(((1R,2R)-2-Hydroxycyclohexyl)amino)benzo[d]thiazole-6-carbonitrilewas synthesized as a white solid (1.8 g, 69%) using a procedureanalogous to that described in Step 6 of Example 3, substituting2-(methylsulfinyl)benzo[d]thiazole-6-carbonitrile from Step 1 of thisExample for6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazoleused in Example 3. LCMS (ESI) m/z 274 (M+H)⁺.

Step 3: To a stirred mixture of2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazole-6-carbonitrile(1.2 g, 4.5 mmol) from Step 2 of this Example and 2,2-dimethoxypropane(4.7 g, 45 mmol) in 1,4-dioxane (30 mL) were added para-toluenesulfonicacid (89 mg, 0.5 mmol) and molecular sieves (4 Å) and the mixture washeated at reflux for 15 h. The mixture was cooled to rt, filtered, andthe filtrate was concentrated under reduced pressure. The residue waspurified via silica gel flash chromatography to afford2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazole-6-carbonitrile(700 mg, 50%) as a white solid. LCMS (ESI) m/z 314 (M+H)⁺.

Step 4: To a stirred mixture of2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazole-6-carbonitrile(260 mg, 0.8 mmol) from Step 3 of this Example in THF (10 mL) at 0° C.was added LAH (3.3 mL of a 1M solution in THF, 3.3 mmol). The mixturewas allowed to warm slowly to rt and stirred for 15 h. The mixture wasagain cooled to 0° C. and Na₂SO₄.10H₂O was added slowly. The mixture wasstirred for 2 h, filtered, and the filtrate was concentrated underreduced pressure to afford(2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol-6-yl)methanamine (237 mg). The material was usedin the next step without further purification. LCMS (ESI) m/z 318(M+H)⁺.

Step 5: To a stirred mixture of(2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol-6-yl)methanamine (236 mg, 0.7 mmol) from Step 4of this Example and DIEA (388 μL, 2.2 mmol) at 0° C. under argon wasadded 4,6-dichloro-5-nitropyrimidine (159 mg, 0.8 mmol) in one portion.The mixture was stirred for 4 h and then concentrated under reducedpressure. The residue was purified by silica gel flash chromatography(eluting with a gradient of 100% hexanes to 50% EtOAc in hexanes) toafford 6-chloro-N-((2-((3 aR, 7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol-6-yl)methyl)-5-nitropyrimidin-4-amine (153 mg,43%) as an oil. ¹H NMR (300 MHz, CDCl₃) δ 8.45 (s, 1H), 7.81 (br s, 1H),7.57-7.63 (m, 2H), 7.22-7.31 (m, 1H), 4.85 (d, J=5.7 Hz, 2H), 3.11 (m,1H), 2.82 (m, 1H), 2.11-2.16 (m, 1H), 1.90 (m, 1H), 1.80 (s, 3H),1.51-1.69 (m, 5H), 1.19-1.49 (m, 4H). LCMS (ESI) m/z 475 (M+H)⁺.

Step 6: To a stirred mixture of6-chloro-N-((2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol-6-yl)methyl)-5-nitropyrimidin-4-amine (153 mg,0.3 mmol) from Step 5 of this Example in MeOH (5 mL) and EtOAc (5 mL)was added Pd 10% wt. on carbon (20 mg, 0.02 mmol). Hydrogen gas wasbubbled through the stirred mixture for 2 min, then stirring wascontinued for 15 h under 1 atm of H₂. The mixture was filtered and thefiltrate was concentrated under reduced pressure to afford N⁴-((2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol-6-yl)methyl)pyrimidine-4,5-diamine as an oil(155 mg). The material was used in the next step without furtherpurification. LCMS (ESI) m/z 411 (M+H)⁺.

Step 7:(3aR,7aR)-3-(6-((9H-Purin-9-yl)methyl)benzo[d]thiazol-2-yl)-2,2-dimethyloctahydrobenzo[d]oxazolewas synthesized as an oil (220 mg) using a procedure analogous to thatdescribed in Step 3 of Example 41, substituting N⁴-((2-((3 aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol-6-yl)methyl)pyrimidine-4,5-diamine from Step 6of this Example for4-bromo-5-methoxy-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamineused in Example 41. LCMS (ESI) m/z 421 (M+H)⁺.

Step 8: A solution of(3aR,7aR)-3-(6-((9H-purin-9-yl)methyl)benzo[d]thiazol-2-yl)-2,2-dimethyloctahydrobenzo[d]oxazole(220 mg, 0.5 mmol) from Step 7 of this Example in TFA (5 mL) and CH₂Cl₂(5 mL) was stirred for 2 h at rt. The mixture was concentrated underreduced pressure and the residue was purified by reverse-phasepreparative HPLC using a mixture of water (5% CH₃CN, 0.05% HCOOH) andCH₃CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18column as the stationary phase to afford(1R,2R)-2-((6-((9H-purin-9-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(7 mg, 4%) as a white powder. ¹H NMR (300 MHz, DMSO-d₆) δ 9.17 (s, 1H),8.96 (s, 1H), 8.74 (s, 1H), 8.01 (d, J=7.5 Hz, 1H), 7.68 (d, J=1.1 Hz,1H), 7.17-7.36 (m, 2H), 5.50 (s, 2H), 4.78 (d, J=4.5 Hz, 1H), 3.52 (m,1H), 3.33 (m, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.57-1.67 (m, 2H),1.11-1.34 (m, 4H). LCMS (ESI) m/z 381 (M+H)⁺.

Example 49 Preparation of(1R,2R)-1-((6-((5-bromo-6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol

Step 1:6-((5-Bromo-6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazolewas synthesized as a white foam (200 mg) using a procedure analogous tothat described in Step 6 of Example 36, substituting6-((5-bromo-6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazoleregioisomer 1 from Step 3 of Example 47 for6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole usedin Example 36. LCMS (ESI) m/z 436 and 438 (M+H)⁺.

Step 2: To a suspension of6-((5-bromo-6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole(279 mg, 0.07 mmol) and (1R,2R)-1-amino-2,3-dihydro-1H-inden-2-ol (30mg, 0.2 mmol) was added DIEA (60 μL, 0.3 mmol). The mixture was heatedin a Biotage microwave synthesizer at 160° C. in a sealed tube for 30min. The mixture was then subjected to purification by reverse-phasepreparative HPLC using a mixture of water (5% CH₃CN, 0.05% HCOOH) andCH₃CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18column as the stationary phase to afford(1R,2R)-1-((6-((5-bromo-6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol(7 mg, 20%) as a white powder. ¹H NMR (300 MHz, DMSO-d₆) δ 8.48 (d,J=7.9 Hz, 1H), 8.31 (s, 1H), 7.86 (s, 1H), 7.72 (s, 1H), 7.33-7.41 (m,2H), 7.28 (m, 1H), 7.12-7.24 (m, 4H), 5.49 (s, 2H), 5.17 (t, J=7.1 Hz,1H), 4.29 (br s, 1H), 3.87 (s, 3H), 3.16 (dd, J=7.0, 15.6 Hz, 1H), 2.74(dd, J=7.3, 15.5 Hz, 1H). LCMS (ESI) m/z 522 and 524 (M+H)⁺.

Example 50 Preparation of(±)-2-((6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cycloheptanol

Step 1: To a stirred mixture of (±)-2-azidocycloheptanol (190 mg, 1.2mmol) in THF (1 mL) and H₂O (100 μL) was added PPh₃ (321 mg, 1.2 mmol).The mixture was stirred at rt for 15 h, then concentrated under reducedpressure. The residue was purified via silica gel flash chromatographyeluting with 100:15:1, CH₂Cl₂:MeOH:TEA to afford(±)-2-aminocycloheptanol (103 mg, 50%) as a white solid. LCMS(ELSD)(ESI) m/z 130 (M+H)⁺.

Step 2:(±)-2-((6-((5,6-Dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cycloheptanolwas synthesized as a white powder (39 mg, 16%) using a procedureanalogous to that described in Example 27, substituting(±)-2-aminocycloheptanol from Step 1 of this Example for 2-ethoxyanilineused in Example 27. ¹H NMR (300 MHz, DMSO-d₆) δ 8.15 (s, 1H), 8.05 (d,J=7.3 Hz, 1H), 7.63 (d, J=1.1 Hz, 1H), 7.30 (m, 1H), 7.13-7.24 (m, 3H),5.41 (s, 2H), 4.80 (d, J=4.1 Hz, 1H), 3.64-3.81 (m, 8H), 3.58 (br s,1H), 1.23-1.99 (m, 9H). LCMS (ESI) m/z 453 (M+H)⁺.

Example 51 Preparation of(1R,2R)-2-((6-((6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: To a suspension of6-((5-bromo-6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole(502 mg, 1 mmol) from Step 1 of Example 49 and(1R,2R)-2-aminocyclohexanol in DMA (4 mL) was added DIEA (1 mL, 6 mmol).The mixture was heated in a sealed tube at 110° C. for 16 h. The mixturewas cooled to rt and added dropwise with stirring to H₂O (200 mL). Afterthe mixture was stirred for 30 min, the solid was collected byfiltration to afford(1R,2R)-2-((6-((5-bromo-6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(443 mg, 80%) as a tan solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.30 (s, 1H),7.99 (d, J=7.5 Hz, 1H), 7.86 (s, 1H), 7.66 (d, J=1.1 Hz, 1H), 7.37 (s,1H), 7.30 (m, 1H), 7.22 (m, 1H), 5.46 (s, 2H), 4.76 (d, J=5.1 Hz, 1H),3.86 (s, 3H), 3.53 (m, 1H), 3.33 (m, 1H), 2.03 (m, 1H), 1.88 (m 1H),1.55-1.69 (m 2H), 1.11-1.33 (m, 4H). LCMS (ESI) m/z 486 and 488 (M+H)⁺.

Step 2: A suspension of(1R,2R)-2-((6-((5-bromo-6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(30 mg, 0.06 mmol) from Step 1 of this Example and1-methylpyrazole-4-boronic acid pinacol ester (26 mg, 0.1 mmol) in DME(300 L) was added aq 2M K₂CO₃ (150 μL, 0.2 mmol). Argon was bubbled intothe mixture for 5 min followed by the addition ofdichlorobis(triphenylphosphine)palladium II (4 mg, 0.006 mmol). Argonwas bubbled into the mixture for an additional 5 min and then themixture was heated in a sealed tube for 15 h. The mixture was cooled tort and then partitioned between EtOAc (100 mL) and water (50 mL). TheEtOAc layer was separated and concentrated under reduced pressure. Theresidue was purified by reverse-phase preparative HPLC, using a mixtureof water (5% CH₃CN, 0.05% HCOOH) and CH₃CN (0.05% HCOOH) as the mobilephase and Varian Pursuit XRs C18 column as the stationary phase toafford(1R,2R)-2-((6-((6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(16 mg, 53%) as a white powder. ¹H NMR (300 MHz, DMSO-d₆) δ 8.21 (s,1H), 7.97-8.06 (m, 2H), 7.87 (s, 1H), 7.80 (s, 1H), 7.66 (d, J=1.1 Hz,1H), 7.27-7.33 (m, 1H), 7.19-7.25 (m, 2H), 5.44 (s, 2H), 4.78 (d, J=4.3Hz, 1H), 3.85 (s, 6H), 3.51 (m, 1H), 3.33 (m, 1H), 2.03 (m, 1H), 1.87(m, 1H), 1.56-1.66 (m, 2H), 1.12-1.32 (m, 4H). LCMS (ESI) m/z 489(M+H)⁺.

Example 52 Preparation of(1R,2R)-2-((6-((5-methoxy-6-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

(1R,2R)-2-((6-((5-Methoxy-6-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(19 mg, 55%) was synthesized as a white powder using a procedureanalogous to that described in Step 2 of Example 51, substituting(1R,2R)-2-((6-((6-bromo-5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolfrom Step 5 of Example 47 for(1R,2R)-2-((6-((5-bromo-6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolused in Example 51. ¹H NMR (300 MHz, DMSO-d₆) δ 8.27 (s, 1H), 8.06 (s,1H), 7.99 (d, J=7.3 Hz, 1H), 7.88 (s, 1H), 7.77 (s, 1H), 7.68 (d, J=1.1Hz, 1H), 7.18-7.33 (m, 3H), 5.44 (s, 2H), 4.77 (d, J=4.5 Hz, 1H), 3.86(s, 6H), 3.50 (m, 1H), 3.33 (m, 1H), 2.02 (m, 1H), 1.86 (m, 1H),1.55-1.65 (m, 2H), 1.10-1.31 (m, 4H). LCMS (ESI) m/z 489 (M+H)⁺.

Example 53 Preparation of1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-5-methoxy-1H-benzo[d]imidazole-6-carbonitrile

To a suspension of(1R,2R)-2-((6-((6-bromo-5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(50 mg, 0.1 mmol) from Step 5 of Example 47 in DMF (1.5 mL) was addedzinc cyanide (24 mg, 0.2 mmol). Argon was bubbled into the mixture for 5min followed by the addition of 1,1′-bis(diphenylphosphino)ferrocene (9mg, 0.02 mmol) and tris(dibenzylideneacetone)dipalladium (9 mg, 0.01mmol). Argon was bubbled into the mixture for an additional 5 min. Thereaction vessel was sealed and the mixture was heated at 110° C. for 15h. The mixture was cooled to rt and argon was again bubbled into themixture for 5 min. Additional zinc cyanide (24 mg, 0.2 mmol),1,1′-Bis(diphenylphosphino)ferrocene (9 mg, 0.02 mmol) andtris(dibenzylideneacetone)dipalladium (9 mg, 0.01 mmol) were added tothe mixture, and the reaction vessel was resealed and heated for 5 h.The mixture was cooled to rt, filtered, and the filtrate was purified byreverse-phase preparative HPLC using a mixture of water (5% CH₃CN, 0.05%HCOOH) and CH₃CN (0.05% HCOOH) as the mobile phase and Varian PursuitXRs C18 column as the stationary phase to afford1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-5-methoxy-1H-benzo[d]imidazole-6-carbonitrile(18 mg, 41%) as a white powder. ¹H NMR (300 MHz, DMSO-d₆) δ 8.60 (s,1H), 8.12 (s, 1H), 8.01 (d, J=7.3 Hz, 1H), 7.70 (d, J=0.9 Hz, 1H), 7.43(s, 1H), 7.20-7.34 (m, 2H), 5.46 (s, 2H), 4.76 (d, J=4.9 Hz, 1H), 3.90(s, 3H), 3.51 (m, 1H), 3.33 (m, 1H), 2.03 (m, 1H), 1.87 (m, 1H),1.57-1.67 (m, 2H), 1.15-1.34 (m, 4H). LCMS (ESI) m/z 434 (M+H)⁺

Example 54 Preparation of(R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanone

(1R,2R)-2-((6-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolfrom Example 3 (188 mg, 0.50 mmol) was stirred in a mixture ofDCM/MeCN/DMA (4:4:2, v/v/v) at rt. Dess-Martin periodinane (254 mg, 0.60mmol) was added and the mixture was stirred at rt for 30 min beforeanother batch of periodinane (254 mg, 0.60 mmol) was added. Theresulting mixture was heated at 55° C. for 4 h, then another batch ofperiodinane (254 mg, 0.60 mmol) was added and the reaction mixture washeated at 60° C. for 6 h. LCMS showed that the reaction was mostlycomplete. The mixture was then cooled to rt and partitioned between DCMand 3% aq NaOH, and then the organic layer was washed with brine, driedover MgSO₄, and concentrated under reduced pressure. The residue waspurified by silica gel chromatography eluting with 0-100% EtOAc inhexanes to give(R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanone(150 mg, 80%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.60 (s,1H), 8.38 (dd, J=1.2, 4.8 Hz, 1H), 8.22 (d, J=7.3 Hz, 1H), 8.09 (dd,J=1.3, 8.1 Hz, 1H), 7.70 (d, J=1.1 Hz, 1H), 7.26-7.35 (m, 2H), 7.19-7.26(m, 1H), 5.49 (s, 2H), 4.68 (td, J=6.5, 12.8 Hz, 1H), 2.53-2.67 (m, 1H),2.42 (ddd, J=2.7, 5.9, 12.3 Hz, 1H), 2.30 (d, J=13.4 Hz, 1H), 1.94-2.12(m, 1H), 1.82 (br s, 2H), 1.38-1.66 (m, 2H). LCMS (ESI) m/z 378 (M+H)⁺.

Example 55 Preparation of(1R,2R)-2-((6-((6-chloro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1:5-Chloro-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3-nitropyridin-2-aminewas synthesized as a yellow foam (126 mg, 29%) using a procedureanalogous to that described in Step 1 of Example 41, substituting5-chloro-3-nitropyridin-2-amine for 4-bromo-5-methoxy-2-nitroanilineused in Example 41. LCMS (ESI) m/z 367 (M+H)⁺.

Step 2: Crude5-chloro-N²-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyridine-2,3-diaminewas synthesized as a yellow solid using a procedure analogous to thatdescribe in Step 2 of Example 41, substituting5-chloro-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3-nitropyridin-2-aminefrom Step 1 of this Example for4-bromo-5-methoxy-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroanilineused in Example 41. The residue was purified by silica gel flashchromatography eluting with a gradient of 100% hexanes to 100% EtOAc toafford5-chloro-N²-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyridine-2,3-diamine(75 mg, 65%). LCMS (ESI) m/z 337 (M+H)⁺.

Step 3:6-((6-Chloro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazolewas synthesized as a white foam (62 mg, 80%) using a procedure analogousto that described in Step 3 of Example 41, substituting5-chloro-N²-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyridine-2,3-diaminefrom Step 2 of this Example for4-bromo-5-methoxy-N¹-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamineused in Example 41. LCMS (ESI) m/z 347 (M+H)⁺.

Step 4: 6-((6-Chloro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole was synthesized as a white foam (111 mg) usinga procedure analogous to that described in Step 6 of Example 36,substituting6-((6-chloro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazolefrom Step 3 of this Example for6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole usedin Example 36. LCMS (ESI) m/z 363 (M+H)⁺.

Step 5:(1R,2R)-2-((6-((6-Chloro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolwas synthesized as a white powder (35 mg, 47%) using a procedureanalogous to that described in Step 7 of Example 36, substituting6-((6-chloro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazolefrom Step 4 of this Example for6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazoleused in Example 36. ¹H NMR (300 MHz, DMSO-d₆) δ 8.69 (s, 1H), 8.42 (d,J=2.1 Hz, 1H), 8.28 (d, J=2.3 Hz, 1H), 7.97 (d, J=7.5 Hz, 1H), 7.66 (d,J=1.3 Hz, 1H), 7.29 (m, 1H), 7.21 (m, 1H), 5.48 (s, 2H), 4.74 (d, J=5.1Hz, 1H), 3.51 (m, 1H), 3.33 (m, 1H), 2.02 (m, 1H), 1.87 (m, 1H),1.55-1.65 (m, 2H), 1.12-1.31 (m, 4H). LCMS (ESI) m/z 414 (M+H)⁺.

Example 56 Preparation of(1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol

Step 1: To a stirred mixture of methyl2-mercaptobenzo[d]oxazole-6-carboxylate (5 g, 23.92 mmol) and solidK₂CO₃ (9.9 g, 71.76 mmol) in anhydrous DMF (50 mL) at rt was addedmethyl iodide (10.2 g, 71.76 mmol). The mixture was stirred at rt for 15h. The reaction mixture was diluted with water then extracted with DCM(×3). The combined organic layers were washed with water and 2 M aq HCl.The organic layer was separated and dried over MgSO₄, filtered, andconcentrated under reduced pressure to afford methyl2-(methylthio)benzo[d]oxazole-6-carboxylate (4.24 g, 80%) as a lightpink solid that did not require further purification. ¹H NMR (300 MHz,CDCl₃) δ 8.12 (d, J=1.1 Hz, 1H), 8.04 (dd, J=1.1, 8.3 Hz, 1H), 7.61 (d,J=8.3 Hz, 1H), 3.95 (s, 3H), 2.79 (s, 3H). LCMS (ESI) m/z 224 (M+H)⁺.

Step 2: To a stirred solution of methyl2-(methylthio)benzo[d]oxazole-6-carboxylate (4.24 g, 19 mmol) from Step1 of this Example in anhydrous DCM (100 mL) under an argon atmosphere at−78° C. was added dropwise diisobutylaluminum hydride (1.0 M solution inDCM, 40 mL, 40 mmol). The mixture was allowed to warm to −30° C. over 2h. The reaction was quenched by addition of saturated aq sodiumpotassium tartrate and the resulting mixture stirred at rt for anadditional 15 h. The organic layer was separated and the aqueous layerextracted with additional DCM (×2). The combined organic layers werewashed with water dried over MgSO₄, filtered, and concentrated underreduced pressure to afford (2-(methylthio)benzo[d]oxazol-6-yl)methanol(2 g, 54%) as a tan solid that did not require further purification. ¹HNMR (300 MHz, DMSO-d₆) δ 7.51-7.61 (m, 2H), 7.28 (d, J=8.3 Hz, 1H), 5.34(t, J=5.7 Hz, 1H), 4.59 (d, J=5.7 Hz, 2H), 2.76 (s, 3H). LCMS (ESI) m/z196 (M+H)⁺.

Step 3: To a stirred solution of(2-(methylthio)benzo[d]oxazol-6-yl)methanol (2 g, 10.26 mmol) from Step2 of this Example in a mixture of anhydrous DMF (0.5 mL) and anhydrousDCM (100 mL) at 0° C. was added dropwise thionyl chloride (4 mL, 55mmol). The mixture was allowed to warm to rt and stirred for a further40 min. The mixture was concentrated under reduced pressure and theresidue was partitioned between saturated aq NaHCO₃ and a 10:1 mixtureof DCM:MeOH. The organic layer was separated and dried over MgSO₄,filtered, and concentrated under reduced pressure to afford6-(chloromethyl)-2-(methylthio)benzo[d]oxazole (2 g, 92%) as a lightpink solid which did not require further purification. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 7.75 (d, J=1.3 Hz, 1H), 7.63 (d, J=8.1 Hz, 1H), 7.43 (dd,J=1.3, 8.1 Hz, 1H), 4.89 (s, 2H), 2.77 (s, 3H). LCMS (ESI) m/z 214(M+H)⁺.

Step 4: To a stirred solution of 4-azabenzimidazole (304 mg, 2.55 mmol)in anhydrous DMF (10 mL) at 0° C. was added in one portion sodiumhydride (60% dispersion in mineral oil, 107 mg, 2.68 mmol) and themixture was stirred at 0° C. for 20 min. The mixture was allowed to warmto rt and stirred for a further 20 min. To the reaction mixture wasadded a solution of 6-(chloromethyl)-2-(methylthio)benzo[d]oxazole (600mg, 2.81 mmol) from Step 3 of this Example in DMF (5 mL). The mixturewas stirred at rt for 15 h. To the reaction mixture was added water andthe mixture was extracted with DCM. The combined organic layers werewashed with brine. The organic layer was separated, dried over MgSO₄,filtered, and the filtrate was concentrated under reduced pressure. Thecrude material was purified by silica gel flash chromatography elutingwith 100% DCM followed by 1% MeOH in DCM to afford6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]oxazole(290 mg, 38%) as a white solid. The regiochemistry of the alkylation wasdetermined by 2-dimensional nuclear Overhauser effect (NOE) experiment.¹H NMR (300 MHz, DMSO-d₆) δ 8.64 (s, 1H), 8.38 (dd, J=1.2, 4.6 Hz, 1H),8.10 (dd, J=1.2, 8.0 Hz, 1H), 7.69 (s, 1H), 7.58 (d, J=8.1 Hz, 1H),7.25-7.41 (m, 2H), 5.61 (s, 2H), 2.73 (s, 3H). LCMS (ESI) m/z 297(M+H)⁺.

Step 5: To a stirred solution of6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]oxazole(290 mg, 0.979 mmol) from Step 4 of this Example in DCM (25 mL) at 0° C.was added 70% meta-chloroperbenzoic acid (582 mg, 2.36 mmol), and themixture was stirred at 0° C. for 2.5 h. To the mixture was addedsaturated aq NaHCO₃ and the organic layer was separated. The aqueouslayer was extracted with DCM and the combined organic layers were washedwith saturated aq NaHCO₃. The organic layer was separated, dried overMgSO₄, filtered, and concentrated under reduced pressure to afford6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole(305 mg, 100%) as a solid which did not require further purification. ¹HNMR (300 MHz, DMSO-d₆) δ 8.67 (s, 1H), 8.38 (d, J=4.5 Hz, 1H), 8.11 (d,J=7.2 Hz, 1H), 7.84-7.94 (m, 2H), 7.52 (d, J=8.3 Hz, 1H), 7.30 (dd,J=4.8, 8.0 Hz, 1H), 5.69 (s, 2H), 3.18 (s, 3H). LCMS (ESI) m/z 313(M+H)⁺.

Step 6: A stirred mixture of6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]oxazole(165 mg, 0.53 mmol) from Step 5 of this Example,(1R,2R)-(−)-2-aminocyclohexanol (122 mg, 1.06 mmol), and DIEA (137 mg,1.06 mmol) in anhydrous DMA (3 mL) was sealed and heated at 100° C. for15 h. The reaction mixture was cooled to rt and purified directly byreverse-phase HPLC using a mixture of water (5% CH₃CN, 0.05% HOAc),CH₃CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenylcolumn as the stationary phase to afford(1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol(44 mg, 23%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.60 (s, 1H),8.39 (dd, J=1.1, 4.7 Hz, 1H), 8.08 (dd, J=1.2, 8.0 Hz, 1H), 7.81 (d,J=7.5 Hz, 1H), 7.40 (s, 1H), 7.29 (dd, J=4.7, 8.1 Hz, 1H), 7.10-7.19 (m,2H), 5.50 (s, 2H), 4.70 (br s, 1H), 3.25-3.45 (m, 2H), 1.83-1.97 (m,2H), 1.57-1.67 (m, 2H), 1.14-1.32 (m, 4H). LCMS (ESI) m/z 364 (M+H)⁺.

Example 57 Preparation of(1R,2R)-1-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]oxazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol

A stirred mixture of6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]oxazole(108 mg, 0.346 mmol) from Step 5 of Example 56,(1R,2R)-(−)-trans-1-amino-2-indanol (104 mg, 0.698 mmol), and DIEA (90mg, 0.698 mmol) in anhydrous DMA (1.5 mL) was sealed and heated in aBiotage microwave synthesizer at 120° C. for 30 min. The reactionmixture was cooled to rt and purified directly by reverse-phase HPLCusing a mixture of water (5% CH₃CN, 0.05% HCOOH) and CH₃CN (0.05% HCOOH)as the mobile phase and Varian Pursuit XRs C-18 column as the stationaryphase to afford(1R,2R)-1-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]oxazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol(35 mg, 26%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.62 (s, 1H),8.36-8.45 (m, 2H), 8.09 (dd, J=1.3, 8.1 Hz, 1H), 7.47 (s, 1H), 7.29 (dd,J=4.7, 8.1 Hz, 1H), 7.12-7.25 (m, 6H), 5.52 (s, 2H), 5.47 (d, J=5.1 Hz,1H), 5.02 (m, 1H), 4.34 (m, 1H), 3.15 (dd, J=7.2, 15.6 Hz, 1H), 2.73(dd, J=7.6, 15.4 Hz, 1H). LCMS (ESI) m/z 398 (M+H)⁺.

Example 58 Preparation of(R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanoneoxime

(R)-2-((6-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanonefrom Example 54 (70 mg, 0.19 mmol) was stirred in EtOH. Pyridine (100μL, excess) and NH₂OH.HCl (100 mg, excess) were added and the resultingmixture was heated at 88° C. for 1 h. LCMS showed that the reaction wascomplete. The mixture was then cooled to rt and purified by HPLC using amixture of water (5% CH₃CN, 0.05% HCOOH) and CH₃CN (0.05% HCOOH) as themobile phase and Varian Pursuit XRs C-18 column as the stationary phaseto afford(R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanoneoxime (53 mg, 73%) as a white powder. ¹H NMR (300 MHz, DMSO-d₆) δ 10.57(s, 1H), 8.60 (s, 1H), 8.38 (d, J=4.0 Hz, 1H), 8.13-8.27 (m, 1H), 8.09(dd, J=0.8, 7.9 Hz, 1H), 7.58-7.76 (m, 1H), 7.10-7.39 (m, 3H), 5.49 (s,2H), 4.33-4.77 (m, 1H), 2.69-2.95 (m, 1H), 1.92-2.38 (m, 2H), 1.26-1.86(m, 5H). LCMS (ESI) m/z 393 (M+H)⁺.

Example 59 Preparation of either(1S,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-1-methylcyclohexanolor(1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-1-methylcyclohexanolEither

(R)-2-((6-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanonefrom Example 54 (60 mg, 0.16 mmol) was stirred in 5 mL of THF at 0° C.under argon. Methyl lithium in THF (1.6 M, 99 μL, 0.16 mmol) was droppedin slowly. The resulting mixture was stirred at rt for 30 min beforemore methyl lithium in THF (495 μL, 0.80 mmol) was added. After 90 min,the reaction was quenched with sat. NH₄Cl (20 mL) and the resultingmixture was extracted with DCM (2×50 mL). The combined organic layerswere washed with brine, dried over MgSO₄, and concentrated under reducedpressure. The residue was purified by silica gel preparative TLC,eluting with 5:95 2N NH₃/MeOH: EtOAc, followed by HPLC using a mixtureof water (5% CH₃CN, 0.05% HCOOH) and CH₃CN (0.05% HCOOH) as the mobilephase and Varian Pursuit XRs C-18 column as the stationary phase toafford two separate diastereoisomers:

The first eluting isomer on reverse-phase HPLC is one of(1S,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-1-methylcyclohexanolor(1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-1-methylcyclohexanol

(5 mg, 8%) as a white powder. ¹H NMR (300 MHz, MeOH-d₄) δ 8.40-8.51 (m,2H), 8.10 (dd, J=0.9, 8.1 Hz, 1H), 7.64 (s, 1H), 7.23-7.43 (m, 3H), 5.57(s, 2H), 3.78-3.92 (m, 1H), 1.56-1.84 (m, 4H), 1.31-1.55 (m, 4H), 1.22(s, 3H). LCMS (ESI) m/z 394 (M+H)⁺.

Example 60 Preparation of either(1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-1-methylcyclohexanolor(1S,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-1-methylcyclohexanolEither

For the two diastereoisomers obtained in Example 59, the second elutingisomer on reverse-phase HPLC is one of(1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-1-methylcyclohexanolor(1S,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-1-methylcyclohexanoland is the alternative to Example 59; obtained as a white powder (4 mg,6%). ¹H NMR (300 MHz, MeOH-d₄) δ 8.28-8.40 (m, 2H), 7.99 (dd, J=1.1, 8.1Hz, 1H), 7.52 (d, J=0.9 Hz, 1H), 7.13-7.35 (m, 3H), 5.45 (s, 2H), 3.58(dd, J=3.9, 11.2 Hz, 1H), 1.17-1.74 (m, 8H), 1.12 (s, 3H). LCMS (ESI)m/z 394 (M+H)⁺.

Example 61 Preparation of(1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol

Step 1: A stirred mixture of 5-bromopyridine-2,3-diamine (5 g, 26.6mmol), formic acid (2.5 mL), and triethylorthoformate (70 mL) was heatedat 100° C. for 2.5 h. The reaction mixture was cooled to rt and thesolid precipitate was collected by filtration, washed with Et₂O anddried to afford 6-bromo-3H-imidazo[4,5-b]pyridine as a solid (3.22 g,61%) which did not require further purification. ¹H NMR (300 MHz,DMSO-d₆) δ 13.14 (br s, 1H), 8.50 (s, 1H), 8.44 (d, J=2.1 Hz, 1H), 8.31(d, J=1.9 Hz, 1H). LCMS (ESI) m/z 198 and 200 (M+H)⁺.

Step 2: To a stirred solution of 6-bromo-3H-imidazo[4,5-b]pyridine (506mg, 2.55 mmol) from Step 1 of this Example in anhydrous DMF (10 mL) at0° C. was added in one portion sodium hydride (60% dispersion in mineraloil, 107 mg, 2.68 mmol), and the mixture was stirred at 0° C. for 30min. To the reaction mixture was added a solution of6-(chloromethyl)-2-(methylthio)benzo[d]oxazole (600 mg, 2.81 mmol) fromStep 3 of Example 56 in DMF (2 mL). The mixture was allowed to warm tort, then stirred for a further 15 h. To the reaction mixture was addedwater and the mixture was extracted with EtOAc. The organic layer wasseparated and the aq layer extracted with additional EtOAc. The combinedorganic layers were washed with water then brine. The organic layer wasseparated, dried over MgSO₄, filtered, and concentrated under reducedpressure. The residue was purified by silica gel flash chromatographyeluting with 100% DCM, followed by 1% MeOH in DCM to afford6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]oxazole(460 mg, 48%) as a white solid. The regiochemistry of the alkylation wasdetermined by 2-dimensional nuclear Overhauser effect (NOE) experiment.¹H NMR (300 MHz, DMSO-d₆) δ 8.70 (s, 1H), 8.48 (d, J=1.9 Hz, 1H), 8.40(d, J=1.9 Hz, 1H), 7.68 (s, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.34 (d, J=8.1Hz, 1H), 5.59 (s, 2H), 2.73 (s, 3H). LCMS (ESI) m/z 375 and 377 (M+H)⁺.

Step 3: To a stirred solution of6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]oxazole(460 mg, 1.23 mmol) from Step 2 of this Example in DCM (25 mL) at 0° C.was added 70% meta-chloroperbenzoic acid (333 mg, 1.35 mmol), and themixture was allowed to warm to rt and stirred for a further 30 min. Tothe mixture was added saturated aq NaHCO₃ and the organic layer wasseparated. The aqueous layer was re-extracted with DCM and the combinedorganic layers were washed with saturated aq NaHCO₃. The organic layerwas separated, dried over MgSO₄, filtered, and concentrated underreduced pressure to afford6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole(481 mg, 100%) as a cream solid which did not require furtherpurification. ¹H NMR (300 MHz, DMSO-d₆) δ 8.73 (s, 1H), 8.40-8.50 (m,2H), 7.84-7.95 (m, 2H), 7.50 (d, J=8.3 Hz, 1H), 5.68 (s, 2H), 3.18 (s,3H). LCMS (ESI) m/z 391 and 393 (M+H)⁺.

Step 4: A stirred mixture of6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole(150 mg, 0.384 mmol) from Step 3 of this Example,(1R,2R)-(−)-2-aminocyclohexanol (88 mg, 0.768 mmol), and DIEA (99 mg,0.768 mmol) in anhydrous DMA (3 mL) in a sealed vial was heated in aBiotage microwave synthesizer at 120° C. for 30 min. After the reactionmixture was cooled to rt, it was purified directly by reverse-phase HPLCusing a mixture of water (5% CH₃CN, 0.05% HCOOH) and CH₃CN (0.05% HCOOH)as the mobile phase and Varian Pursuit XRs C-18 column as the stationaryphase to afford(1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol(64 mg, 38%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.66 (s, 1H),8.49 (d, J=2.0 Hz, 1H), 8.38 (d, J=1.7 Hz, 1H), 7.81 (d, J=7.6 Hz, 1H),7.39 (s, 1H), 7.10-7.16 (m, 2H), 5.48 (s, 2H), 4.69 (d, J=4.2 Hz, 1H),3.30-3.40 (m, 2H), 1.83-1.97 (m, 2H), 1.57-1.67 (m, 2H), 1.15-1.30 (m,4H). LCMS (ESI) m/z 442 and 444 (M+H)⁺.

Example 62 Preparation of(1R,2R)-1-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]oxazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol

A stirred mixture of6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole(150 mg, 0.384 mmol) from Step 3 of Example 61,(1R,2R)-(−)-trans-1-amino-2-indanol (114 mg, 0.768 mmol), and DIEA (99mg, 0.768 mmol) in anhydrous DMA (3 mL) in a sealed vial was heated in aBiotage microwave synthesizer at 120° C. for 30 min. After the reactionmixture was cooled to rt, it was purified directly by reverse-phase HPLCusing a mixture of water (5% CH₃CN, 0.05% HCOOH) and CH₃CN (0.05% HCOOH)as the mobile phase and Varian Pursuit XRs C-18 column as the stationaryphase to afford(1R,2R)-1-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]oxazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol(40 mg, 22%) as a white solid. ¹H NMR (499 MHz, DMSO-d₆) δ 8.68 (s, 1H),8.49 (d, J=2.0 Hz, 1H), 8.36-8.44 (m, 2H), 7.45 (s, 1H), 7.12-7.24 (m,6H), 5.51 (s, 2H), 5.47 (d, J=5.2 Hz, 1H), 5.01 (t, J=7.6 Hz, 1H), 4.34(m, 1H), 3.15 (dd, J=7.1, 15.5 Hz, 1H), 2.73 (dd, J=7.6, 15.5 Hz, 1H).LCMS (ESI) m/z 476 and 478 (M+H)⁺.

Example 63 Preparation of(S)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-2-cyclohexylethanol

Step 1: To a stirred solution of 4-azabenzimidazole (613 mg, 5.15 mmol)in anhydrous DMF (20 mL) at 0° C. was added in one portion sodiumhydride (60% dispersion in mineral oil, 216 mg, 5.41 mmol) and themixture was stirred at 0° C. for 20 min. The mixture was allowed to warmto rt and stirred for a further 20 min. To the reaction mixture wasadded a solution of 6-(chloromethyl)-2-(methylthio)benzo[d]thiazole (1.3g, 5.66 mmol) from Step 4 of Example 36 in DMF (5 mL). The mixture wasstirred at rt for 15 h. To the reaction mixture was added water (300 mL)and the mixture was extracted with DCM (3×50 mL). The combined organiclayers were washed with brine. The organic layer was separated, driedover MgSO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by silica gel flash chromatography (eluting with100% DCM followed by 1% MeOH in DCM) to afford6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole(670 mg, 41%) as a white solid. The regiochemistry of the alkylation wasdetermined by 2-dimensional nuclear Overhauser effect (NOE) experiment.¹H NMR (300 MHz, DMSO-d₆) δ 8.65 (s, 1H), 8.38 (dd, J=1.3, 4.7 Hz, 1H),8.11 (dd, J=1.2, 8.0 Hz, 1H), 8.00 (d, J=1.1 Hz, 1H), 7.81 (d, J=8.5 Hz,1H), 7.46 (dd, J=1.6, 8.4 Hz, 1H), 7.30 (dd, J=4.7, 8.1 Hz, 1H), 5.62(s, 2H), 2.77 (s, 3H). LCMS (ESI) m/z 313 (M+H)⁺.

Step 2: To a stirred solution of6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole(670 mg, 2.15 mmol) in DCM (25 mL) at 0° C. was added 70%meta-chloroperbenzoic acid (582 mg, 2.36 mmol) and the mixture wasstirred at 0° C. for 1 h. To the mixture was added saturated aqueousNaHCO₃ and the organic layer was separated. The aqueous layer wasextracted with DCM and the combined organic layers were washed withsaturated aq NaHCO₃. The organic layer was separated, dried over MgSO₄,filtered, and under reduced pressure to afford 670 mg of a 4:1 mixtureof 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole and6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfonyl)benzo[d]thiazoleas a solid that was not purified further. LCMS (ESI) m/z 329 (M+H)⁺(consistent with6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole)and m/z 345 (M+H)⁺ (consistent with6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfonyl)benzo[d]thiazole).

Step 3: To a stirred mixture of LiAlH₄ (724 mg, 19.08 mmol) in anhydrousTHF (20 mL) at rt was added portionwise L-(+)-2-cyclohexylglycine (1 g,6.36 mmol). The mixture was heated at 80° C. for 4 h. The mixture wascooled to 0° C. and then water (1 mL), 1M aq NaOH (1 mL), and water (3mL) were added sequentially. The mixture was filtered and the filtratewas partitioned between a mixture of DCM, 1M aq NaOH, and saturated aqsodium potassium tartrate. The organic layer was separated and furtherwashed with 1M aq NaOH. The organic layer was separated, dried overMgSO₄, filtered, and concentrated under reduced pressure to afford(S)-2-amino-2-cyclohexylethanol (500 mg) which was not purified further.LCMS (ESI) m/z 144 (M+H)⁺.

Step 4: A 4:1 mixture of6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole and6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfonyl)benzo[d]thiazole(60 mg) from Step 2 of this Example was dissolved in anhydrous DMA (1.5mL) and to this solution were added (S)-2-amino-2-cyclohexylethanol (52mg, 0.366 mmol) from Step 3 of this Example and DIEA (94 mg, 0.732mmol). The reaction vessel was sealed and the mixture was heated in aBiotage microwave synthesizer at 150° C. for 30 min. LCMS analysisindicated that the reaction was not complete. To the reaction mixturewas added additional (S)-2-amino-2-cyclohexylethanol (52 mg, 0.366mmol). The reaction vessel was sealed and the miexture was heated in aBiotage microwave synthesizer at 150° C. for 40 min. After cooling tort, the mixture was purified directly by reverse-phase HPLC using amixture of water (5% CH₃CN, 0.05% HCOOH) and CH₃CN (0.05% HCOOH) as themobile phase and Varian Pursuit XRs C-18 column as the stationary phaseto afford(S)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-2-cyclohexylethanol(4 mg) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.58 (s, 1H), 8.37(m, 1H), 8.08 (m, 1H), 7.84 (d, J=8.9 Hz, 1H), 7.66 (s, 1H), 7.18-7.31(m, 3H), 5.48 (s, 2H), 3.71 (m, 1H), 3.50 (m, 1H), 1.54-1.77 (m, 7H),0.95-1.24 (m, 6H). LCMS (ESI) m/z 408 (M+H)⁺.

Example 64 Preparation of(R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-2-cyclohexylethanol

Step 1: To a stirred mixture of LiAlH₄ (724 mg, 19.08 mmol) in anhydrousTHF (20 mL) at rt was added portionwise 2-cyclohexyl-D-glycine (1 g,6.36 mmol). The mixture was heated at 80° C. for 4 h. The mixture wascooled to 0° C. and then water (1 mL), 1M aq NaOH (1 mL), and water (3mL) were added sequentially. The mixture was filtered and the filtratewas partitioned between a mixture of DCM, 1M aq NaOH, and saturated aqsodium potassium tartrate. The organic layer was separated and furtherwashed with 1M aq NaOH. The organic was separated, dried over MgSO₄,filtered, and concentrated under reduced pressure to afford(R)-2-amino-2-cyclohexylethanol (400 mg) which was not purified further.LCMS (ESI) m/z 144 (M+H)⁺.

Step 2: A 4:1 mixture of6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole and6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfonyl)benzo[d]thiazole(120 mg) from Step 2 of Example 63 was dissolved in anhydrous DMA (2mL), and then (R)-2-amino-2-cyclohexylethanol (209 mg, 1.46 mmol) fromStep 1 of this Example and DIEA (188 mg, 1.46 mmol) were added. Thereaction vessel was sealed and the mixture was heated with stirring at120° C. for 15 h. After cooling to rt, the mixture was purified directlyby reverse-phase HPLC using a mixture of water (5% CH₃CN, 0.05% HCOOH)and CH₃CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18column as the stationary phase to afford(R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-2-cyclohexylethanol(18 mg) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.59 (s, 1H), 8.38(m, 1H), 8.09 (dd, J=1.0, 8.0 Hz, 1H), 7.85 (d, J=8.9 Hz, 1H), 7.66 (s,1H), 7.18-7.32 (m, 3H), 5.48 (s, 2H), 4.70 (br s, 1H), 3.72 (m, 1H),3.50 (m, 2H), 1.54-1.77 (m, 6H), 0.94-1.23 (m, 5H). LCMS (ESI) m/z 408(M+H)⁺.

Example 65 Preparation of1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-6-methoxy-1H-benzo[d]imidazole-5-carbonitrile

1-((2-(((1R,2R)-2-Hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-6-methoxy-1H-benzo[d]imidazole-5-carbonitrilewas synthesized as a white powder (20 mg, 45%) using a procedureanalogous to that described in Example 53, substituting(1R,2R)-2-((6-((5-bromo-6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolfor(1R,2R)-2-((6-((6-bromo-5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolused in example 53. ¹H NMR (300 MHz, DMSO-d₆) δ 8.60 (s, 1H), 8.12 (s,1H), 8.01 (d, J=7.3 Hz, 1H), 7.70 (d, J=0.9 Hz, 1H), 7.43 (s, 1H),7.20-7.34 (m, 2H), 5.46 (s, 2H), 4.76 (d, J=4.9 Hz, 1H), 3.90 (s, 3H),3.51 (m, 1H), 3.33 (m, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.57-1.67 (m,2H), 1.15-1.34 (m, 4H). LCMS (ESI) m/z 434 (M+H)⁺.

Example 66 Preparation of((1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)methanol

Step 1: To a stirred mixture of LiAlH₄ (796 mg, 20.97 mmol) in anhydrousTHF (20 mL) at rt was added portion-wise(1R,2R)-2-aminocyclohexanecarboxylic acid (1 g, 6.99 mmol). The mixturewas heated at 80° C. for 4 h before it was cooled to 0° C. Water (1 mL),1M aq NaOH (1 mL), and water (3 mL) were added sequentially. The mixturewas filtered and the filtrate partitioned between a mixture of DCM, 1Maq NaOH, and saturated aq sodium potassium tartrate. The organic layerwas separated and washed with 1M aq NaOH. The organic layer wasseparated, dried over MgSO₄, filtered, and under reduced pressure toafford ((1R,2R)-2-aminocyclohexyl)methanol (180 mg) which was notpurified further. LCMS (ESI) m/z 130 (M+H)⁺.

Step 2: A 4:1 mixture of6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole and6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfonyl)benzo[d]thiazole(120 mg) from Step 2 of Example 63 was dissolved in anhydrous DMA (2mL), and then ((1R,2R)-2-aminocyclohexyl)methanol (180 mg, 1.40 mmol)from Step 1 of this Example and DIEA (188 mg, 1.46 mmol) were added. Thereaction vessel was sealed and the mixture was heated with stirring at120° C. for 4.5 h. After cooling to rt, the mixture was purifieddirectly by reverse-phase HPLC using a mixture of water (5% CH₃CN, 0.05%HCOOH) and CH₃CN (0.05% HCOOH) as the mobile phase and Varian PursuitXRs C-18 column as the stationary phase to afford((1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)methanol.

(41 mg) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.59 (s, 1H), 8.38(dd, J=1.1, 4.7 Hz, 1H), 8.09 (dd, J=1.2, 8.0 Hz, 1H), 8.00 (d, J=8.3Hz, 1H), 7.67 (s, 1H), 7.20-7.32 (m, 3H), 5.49 (s, 2H), 4.48 (br s, 1H),3.55 (m, 2H), 1.99 (m, 1H), 1.82 (m, 1H), 1.60-1.75 (m, 2H), 1.10-1.43(m, 6H). LCMS (ESI) m/z 394 (M+H)⁺.

Example 67 Preparation of(1R,2R)-2-((6-((6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

To a mixture of(1R,2R)-2-((6-((5-bromo-6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(100 mg, 0.2 mmol) from Step 1 of Example 51 in 1,4-dioxane (1.4 mL) andaq 1 NNaOH (300 μL) was added zinc powder (134 mg, 2 mmol). The mixturewas heated at 80° C. for 55 h. The mixture was cooled to rt, filtered,and the filtrate was purified by reverse-phase preparative HPLC using amixture of water (5% CH₃CN, 0.05% HCOOH) and CH₃CN (0.05% HCOOH) as themobile phase and Varian Pursuit XRs C18 column as the stationary phaseto afford(1R,2R)-2-((6-((6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(45 mg, 56%) as a white powder. ¹H NMR (500 MHz, DMSO-d₆) δ 8.23 (s,1H), 7.98 (d, J=7.6 Hz, 1H), 7.64 (d, J=1.0 Hz, 1H), 7.51 (d, J=8.6 Hz,1H), 7.29 (d, J=8.4 Hz, 1H), 7.20 (dd, J=1.4, 8.2 Hz, 1H), 7.12 (d,J=2.2 Hz, 1H), 6.80 (dd, J=2.3, 8.7 Hz, 1H), 5.41 (s, 2H), 4.76 (m, 1H),3.76 (s, 3H), 3.51 (m, 1H), 3.33 (m, 1H), 2.03 (m, 1H), 1.87 (m, 1H),1.56-1.66 (m, 2H), 1.14-1.29 (m, 4H). LCMS (ESI) m/z 410 (M+H)⁺.

Example 68 Preparation of(1R,2R)-2-((6-((5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

(1R,2R)-2-((6-((5-Methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolwas synthesized as a white powder (39 mg, 53%) using a procedureanalogous to that described in Example 67, substituting(1R,2R)-2-((6-((6-bromo-5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolfrom Step 5 of Example 47 for(1R,2R)-2-((6-((5-bromo-6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolused in Example 67. ¹H NMR (500 MHz, DMSO-d₆) δ 8.31 (s, 1H), 7.99 (d,J=7.6 Hz, 1H), 7.62 (s, 1H), 7.40 (d, J=8.9 Hz, 1H), 7.28 (d, J=8.4 Hz,1H), 7.13-7.19 (m, 2H), 6.82 (dd, J=2.2, 8.9 Hz, 1H), 5.41 (s, 2H), 4.78(m, 1H), 3.75 (s, 3H), 3.50 (m, 1H), 3.33 (m, 1H), 2.03 (m, 1H), 1.87(m, 1H), 1.56-1.66 (m, 2H), 1.13-1.29 (m, 4H). LCMS (ESI) m/z 410(M+H)⁺.

Example 69 Preparation of(1R,2R)-1-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol

A stirred mixture of6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole(120 mg, 0.346 mmol) from Step 4 of Example 70,(1R,2R)-(−)-trans-1-amino-2-indanol (103 mg, 0.692 mmol), and DIEA (89mg, 0.692 mmol) in anhydrous DMA (2.5 mL) was heated in a Biotagemicrowave synthesizer at 150° C. for 30 min. LCMS analysis indicatedthat the reaction was incomplete. Additional(1R,2R)-(−)-trans-1-amino-2-indanol (103 mg, 0.692 mmol) and DIEA (89mg, 0.692 mmol) were added and the mixture was further heated in aBiotage microwave synthesizer at 150° C. for 2 h. After the reactionmixture was cooled to rt, it was purified directly by reverse-phase HPLCusing a mixture of water (5% CH₃CN, 0.05% HCOOH) and CH₃CN (0.05% HCOOH)as the mobile phase and Varian Pursuit XRs C-18 column as the stationaryphase to afford(1R,2R)-1-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol(24 mg, 16%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.70 (s, 1H),8.40-8.50 (m, 2H), 8.09 (dd, J=2.6, 9.4 Hz, 1H), 7.73 (d, J=1.1 Hz, 1H),7.32-7.39 (m, 1H), 7.10-7.31 (m, 5H), 5.47-6.00 (m, 3H), 5.18 (t, J=7.1Hz, 1H), 4.30 (d, J=3.6 Hz, 1H), 3.16 (dd, J=7.0, 15.6 Hz, 1H), 2.74(dd, J=7.1, 15.5 Hz, 1H). LCMS (ESI) m/z 432 (M+H)⁺.

Example 70 Preparation of(1R,2R)-2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: To a stirred mixture of 2-amino-5-fluoro-3-nitropyridine (2.46g, 15.66 mmol) in a mixture of glacial HOAc (10 mL) and MeOH (20 mL) at0° C. was added zinc dust (5.09 g, 78.3 mmol) portion-wise, and themixture was allowed to warm slowly to rt. After stirring at rt for 15 h,the mixture was filtered through Celite and the filtrate wasconcentrated under reduced pressure. The residue was partitioned betweenEtOAc and saturated aq NaHCO₃. The organic layer was separated and theaqueous layer was extracted with additional EtOAc. The combined organiclayers were dried over MgSO₄, filtered, and concentrated under reducedpressure to afford 5-fluoropyridine-2,3-diamine (1.13 g) as a solidwhich was not purified further. LCMS (ESI) m/z 128 (M+H)⁺.

Step 2: A stirred mixture of 5-fluoropyridine-2,3-diamine (1.13 g) fromStep 1 of this Example, formic acid (0.5 mL), and triethylorthoformate(15 mL) was heated at 100° C. for 1 h. The reaction mixture was cooledto rt, filtered, and the filtrate was concentrated under reducedpressure. The residue was purified via silica gel flash chromatographyeluting with 100% DCM to 10% MeOH in DCM to afford6-fluoro-3H-imidazo[4,5-b]pyridine (760 mg, 36% over two steps) as ayellow solid. ¹H NMR (500 MHz, DMSO-d₆) δ 13.09 (br s, 1H), 8.49 (s,1H), 8.37 (s, 1H), 7.97 (d, J=7.9 Hz, 1H). LCMS (ESI) m/z 138 (M+H)⁺.

Step 3: To a stirred solution of 6-fluoro-3H-imidazo[4,5-b]pyridine (325mg, 2.37 mmol) from Step 2 of this Example in anhydrous DMF (10 mL) at0° C. was added in one portion sodium hydride (60% dispersion in mineraloil, 100 mg, 2.49 mmol), and the mixture was stirred at 0° C. for 30min. To the reaction mixture was added a solution of6-(chloromethyl)-2-(methylthio)benzo[d]thiazole (600 mg, 2.61 mmol) fromStep 4 of Example 36 in DMF (2 mL). The mixture was allowed to warm tort then stirred for a further 15 h. To the reaction mixture was addedwater (250 mL) and the mixture was extracted with DCM (3×100 mL). Thecombined organic layers were washed with water and brine, dried overMgSO₄, filtered, and concentrated under reduced pressure. The residuewas purified by silica gel flash chromatography eluting with 100% DCMfollowed by 1% MeOH in DCM to afford6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole(356 mg, 45%) as a white solid. The regiochemistry of the alkylation wasdetermined by 2-dimensional nuclear Overhauser effect (NOE) experiment.¹H NMR (300 MHz, DMSO-d₆) δ 8.73 (s, 1H), 8.41 (t, J=2.0 Hz, 1H), 8.10(dd, J=2.6, 9.4 Hz, 1H), 7.99 (s, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.46 (dd,J=1.3, 8.3 Hz, 1H), 5.62 (s, 2H), 2.77 (s, 3H). LCMS (ESI) m/z 331(M+H)⁺.

Step 4: To a stirred solution of6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole(350 mg, 1.06 mmol) from Step 3 of this Example in DCM (15 mL) at 0° C.was added 70% meta-chloroperbenzoic acid (287 mg, 1.17 mmol), and themixture was allowed to warm to rt and stirred for a further 2 h. To themixture was added saturated aq NaHCO₃ and the organic layer wasseparated. The aqueous layer was extracted with DCM and the combinedorganic layers were washed with saturated aq NaHCO₃. The organic layerwas separated, dried over MgSO₄, filtered, and concentrated underreduced pressure to afford a solid. The solid was triturated with Et₂O,filtered, then dried to afford6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole(336 mg, 92%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.76 (s,1H), 8.41 (br s, 1H), 8.22 (s, 1H), 8.04-8.15 (m, 2H), 7.63 (d, J=8.3Hz, 1H), 5.70 (s, 2H), 3.06 (s, 3H). LCMS (ESI) m/z 347 (M+H)⁺.

Step 5: A stirred mixture of6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole(90 mg, 0.260 mmol) from Step 4 of this Example,(1R,2R)-(−)-2-aminocyclohexanol (120 mg, 1.03 mmol), and DIEA (133 mg,1.03 mmol) in anhydrous DMA (3 mL) was heated at 125° C. for 15 h. Afterthe reaction mixture had cooled to rt, the mixture was purified directlyby reverse-phase HPLC using a mixture of water (5% CH₃CN, 0.05% HCOOH)and CH₃CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18column as the stationary phase to afford(1R,2R)-2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(41 mg) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.68 (s, 1H), 8.42(s, 1H), 8.08 (dd, J=2.4, 9.4 Hz, 1H), 7.98 (d, J=7.5 Hz, 1H), 7.66 (s,1H), 7.17-7.33 (m, 2H), 5.48 (s, 2H), 4.76 (br s, 1H), 3.45-3.55 (m,2H), 2.03 (m, 1H), 1.87 (m, 1H), 1.55-1.67 (m, 2H), 1.10-1.33 (m, 4H).LCMS (ESI) m/z 398 (M+H)⁺.

Example 71 Preparation of(1R,2R)-2-((6-((3H-imidazo[4,5-c]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1:6-((3H-Imidazo[4,5-c]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole(162 mg, 21%) was obtained as a white solid using a procedure analogousto that described in Step 4 of Example 3, substituting1H-imidazo[4,5-c]pyridine for 3H-imidazo[4,5-b]pyridine used in Example3. The regiochemistry of the alkylation was determined by 2-dimensionalnuclear Overhauser effect (NOE) experiment. ¹H NMR (300 MHz, MeOH-d₄) δ8.82 (d, J=0.8 Hz, 1H), 8.62 (s, 1H), 8.37 (d, J=5.8 Hz, 1H), 7.92 (d,J=1.1 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.75 (dd, J=0.8, 5.7 Hz, 1H),7.46 (dd, J=1.7, 8.3 Hz, 1H), 5.74 (s, 2H), 2.79 (s, 3H). LCMS (ESI) m/z313 (M+H)⁺.

Step 2:(1R,2R)-2-((6-((3H-Imidazo[4,5-c]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(30 mg, 15% over two steps) was obtained as a yellow powder usingprocedures analogous to those described in Step 5 of Example 3 followedby procedures analogous to those described in Step 5 of Example 2,substituting6-((3H-imidazo[4,5-c]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazolefrom Step 1 of this Example for6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazoleused in Example 3 and substituting the product of that reaction for the2-bromo-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazoleused in Example 2. ¹H NMR (300 MHz, DMSO-d₆) δ 8.94 (s, 1H), 8.63 (s,1H), 8.30 (d, J=5.7 Hz, 1H), 8.01 (d, J=7.3 Hz, 1H), 7.74 (s, 1H), 7.65(d, J=5.1 Hz, 1H), 7.18-7.36 (m, 2H), 5.56 (s, 2H), 4.76 (br s, 1H),3.53 (d, J=14.5 Hz, 2H), 2.02 (d, J=10.2 Hz, 1H), 1.86 (s, 1H), 1.61 (brs, 2H), 1.03-1.37 (m, 4H). LCMS (ESI) m/z 380 (M+H)⁺.

Example 72 Preparation of(1R,2R)-2-((6-((1H-imidazo[4,5-c]pyridin-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1:6-((1H-Imidazo[4,5-c]pyridin-1-yl)methyl)-2-(methylthio)benzo[d]thiazole(206 mg, 26%) was obtained as a white solid using a procedure analogousto that described in Step 4 of Example 3, substituting1H-imidazo[4,5-c]pyridine for 3H-imidazo[4,5-b]pyridine used in Example3. The regiochemistry of the alkylation was determined by 2-dimensionalnuclear Overhauser effect (NOE) experiment. ¹H NMR (300 MHz, MeOH-d₄) δ8.95 (s, 1H), 8.53 (s, 1H), 8.31 (d, J=5.8 Hz, 1H), 7.84 (s, 1H), 7.77(d, J=8.3 Hz, 1H), 7.59 (d, J=5.3 Hz, 1H), 7.41 (dd, J=1.4, 8.4 Hz, 1H),5.65 (s, 2H), 2.76 (s, 3H). LCMS (ESI) m/z 313 (M+H)⁺.

Step 2:(1R,2R)-2-((6-((1H-Imidazo[4,5-c]pyridin-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(85 mg, 42% over two steps) was obtained as a yellow powder usingprocedures analogous to those described in Step 5 of Example 3 followedby procedures analogous to those described in Step 5 of Example 2,substituting6-((1H-imidazo[4,5-c]pyridin-1-yl)methyl)-2-(methylthio)benzo[d]thiazolefrom Step 1 of this Example for6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazoleused in Example 3 and substituting the product of that reaction for the2-bromo-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazoleused in Example 2. ¹H NMR (300 MHz, DMSO-d₆) δ 8.95 (br s, 1H), 8.56 (s,1H), 8.31 (d, J=4.9 Hz, 1H), 8.00 (d, J=7.2 Hz, 1H), 7.69 (d, J=1.1 Hz,1H), 7.64 (d, J=5.5 Hz, 1H), 7.26-7.37 (m, 1H), 7.11-7.26 (m, 1H), 5.51(s, 2H), 4.74 (br s, 1H), 3.34 (d, J=4.1 Hz, 2H), 2.02 (d, J=10.2 Hz,1H), 1.86 (br s, 1H), 1.60 (d, J=4.0 Hz, 2H), 0.90-1.37 (m, 4H). LCMS(ESI) m/z 380 (M+H)⁺.

Example 73 Preparation of1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)ethanone

A stirred mixture of(1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(50 mg, 0.109 mmol) from Example 29, tributyl(1-ethoxyvinyl)tin (79 mg,0.218 mmol) and TEA (22 mg, 0.218 mmol) in anhydrous DMF (1 mL) at rtwas flushed with a stream of argon for 15 min. To the resulting mixturewas added tetrakis(triphenylphosphine)palladium (0) (19 mg, 0.0165mmol). The reaction vessel was sealed and the mixture was heated withstirring at 110° C. for 1.5 h. After cooling to rt, aq 2 M HCl (500 μL)was added and the mixture was stirred for 1 h. The reaction mixture waspurified directly by reverse-phase HPLC using a mixture of water (5%CH₃CN, 0.05% HCOOH) and CH₃CN (0.05% HCOOH) as the mobile phase andVarian Pursuit XRs C18 column as the stationary phase to afford1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)ethanone(8 mg, 17%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.00 (d, J=1.5Hz, 1H), 8.76 (s, 1H), 8.64 (s, 1H), 7.99 (d, J=7.5 Hz, 1H), 7.68 (s,1H), 7.20-7.32 (m, 2H), 5.53 (s, 2H), 4.76 (br s, 1H), 3.50 (m, 1H),3.30 (m, 1H), 2.68 (s, 3H), 2.04 (m, 1H), 1.87 (m, 1H), 1.55-1.65 (m,2H), 1.10-1.30 (m, 4H). LCMS (ESI) m/z 422 (M+H)⁺.

Example 74 Preparation of(1R,2R)-2-((6-((6-(methylsulfonyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

A stirred mixture of(1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(100 mg, 0.218 mmol) from Example 29, sodium methanesulfinate (90 mg,0.436 mmol) and unsymmetrical N,N-dimethylethylene diamine (6 mg, 0.066mmol) in anhydrous DMSO (1 mL) at rt was flushed with a stream of argonfor 15 min. To the resulting mixture was added copper (I)trifluoromethane-sulfonate benzene complex (20 mg, 0.0328 mmol). Thereaction vessel was sealed and the mixture was heated with stirring at125° C. for 5 h. After cooling to rt, the reaction mixture was purifieddirectly by reverse-phase HPLC using a mixture of water (5% CH₃CN, 0.05%HOAc) and CH₃CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRsdiphenyl column as the stationary phase to afford(1R,2R)-2-((6-((6-(methylsulfonyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(12 mg, 12%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.85-8.95 (brm, 2H), 8.61 (s, 1H), 8.02 (d, J=7.3 Hz, 1H), 7.69 (s, 1H), 7.18-7.35(m, 2H), 5.56 (s, 2H), 4.79 (br s, 1H), 3.25-3.60 (m, 5H), 2.03 (m, 1H),1.87 (m, 1H), 1.55-1.70 (m, 2H), 1.08-1.36 (m, 4H). LCMS (ESI) m/z 458(M+H)⁺.

Example 75 Preparation of1-(((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)methyl)cyclohexanol

Step 1: To a stirred solution of cyclohexanone cyanohydrin (2 g, 15.98mmol) in anhydrous THF (40 mL) at rt was added portion-wise LiAlH₄ (1.82g, 47.94 mmol). The reaction vessel was sealed and the mixture washeated at 80° C. for 5 h. The mixture was cooled to 0° C. and water (1mL), 1M aq NaOH (1 mL), and water (3 mL) were added sequentially. To theresulting mixture was added DCM and saturated aq sodium potassiumtartrate, and the mixture stirred for 3 h. The organic layer wasseparated and further washed with brine. The organic layer wasseparated, dried over MgSO₄, filtered, and concentrated under reducedpressure to afford 1-(aminomethyl)cyclohexanol (1.3 g) which was notpurified further. LCMS (ESI) m/z 130 (M+H)⁺.

Step 2: A 4:1 mixture of6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole and6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfonyl)benzo[d]thiazole(50 mg) from Step 2 of Example 63 was dissolved in anhydrous DMA (1.5mL), and then 1-(aminomethyl)cyclohexanol (79 mg, 0.608 mmol) from Step1 of this Example and DIEA (98 mg, 0.760 mmol) were added. The reactionvessel was sealed and the mixture was heated with stirring at 125° C.for 15 h. LCMS analysis indicated that the reaction was not complete.Further amounts of 1-(aminomethyl)cyclohexanol (79 mg, 0.608 mmol) fromStep 1 of this Example and DIEA (98 mg, 0.760 mmol) were added and themixture stirred at 125° C. for further 5 h. After cooling to rt, themixture was purified directly by reverse-phase HPLC using a mixture ofwater (5% CH₃CN, 0.05% HOAc) and CH₃CN (0.05% HOAc) as the mobile phaseand Varian Pursuit XRs Diphenyl column as the stationary phase to afford1-(((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)methyl)cyclohexanol(10 mg) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.60 (s, 1H), 8.38(dd, J=1.1, 4.7 Hz, 1H), 8.09 (dd, J=1.2, 8.0 Hz, 1H), 7.96 (t, J=5.6Hz, 1H), 7.67 (s, 1H), 7.19-7.33 (m, 3H), 5.48 (s, 2H), 4.42 (br s, 1H),1.12-1.62 (m, 12H). LCMS (ESI) m/z 394 (M+H)⁺.

Example 76 Preparation of(1-(((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)methyl)cyclohexyl)methanol

Step 1: To a stirred solution of methyl 1-cyanocyclohexanecarboxylate (2g, 11.96 mmol) in anhydrous THF (40 mL) at rt was added portionwiseLiAlH₄ (1.36 g, 35.88 mmol). The reaction vessel was sealed and themixture was heated at 80° C. for 5 h. The mixture was cooled to 0° C.and water (1 mL), 1M aq NaOH (1 mL), and water (3 mL) were addedsequentially. To the resulting mixture were added DCM and saturated aqsodium potassium tartrate, and the mixture was stirred for 3 h. Theorganic layer was separated and further washed with brine. The organiclayer was separated, dried over MgSO₄, filtered, and concentrated underreduced pressure to afford (1-(aminomethyl)cyclohexyl)methanol (1 g)which was not purified further. LCMS (ESI) m/z 144 (M+H)⁺.

Step 2: A 4:1 mixture of6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole and6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfonyl)benzo[d]thiazole(80 mg) from Step 2 of Example 63 was dissolved in anhydrous DMA (2 mL),and (1-(aminomethyl)cyclohexyl)methanol (175 mg, 1.22 mmol) from Step 1of this Example and DIEA (157 mg, 1.22 mmol) were added. The reactionvessel was sealed and the mixture was heated with stirring at 125° C.for 15 h. After cooling to rt, the mixture was purified directly byreverse-phase HPLC using a mixture of water (5% CH₃CN, 0.05% HOAc) andCH₃CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs Diphenylcolumn as the stationary phase to afford1-(((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)methyl)cyclohexanol(22 mg) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.60 (s, 1H), 8.38(dd, J=1.1, 4.7 Hz, 1H), 8.09 (dd, J=1.3, 7.9 Hz, 1H), 7.99 (t, J=5.7Hz, 1H), 7.68 (s, 1H), 7.20-7.33 (m, 3H), 5.49 (s, 2H), 3.33 (d, J=5.8Hz, 2H), 3.21 (s, 1H), 1.21-1.49 (m, 12H). LCMS (ESI) m/z 408 (M+H)⁺.

Example 77 Preparation of(1R,2R)-2-((6-((4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol

Step 1:6-((4-Bromo-1H-imidazol-1-yl)methyl)-2-(methylthio)benzo[d]oxazole wassynthesized as an oil (241 mg, 79%) using a procedure analogous to thatdescribed in Step 5 of Example 36, substituting the 9:1 mixture of(2-(methylthio)benzo[d]oxazol-6-yl)methyl methanesulfonate and6-(chloromethyl)-2-(methylthio)benzo[d]oxazole from Step 1 of Example 34for 6-(chloromethyl)-2-(methylthio)benzo[d]thiazole used in Example 36.The regiochemistry of the alkylation was determined by 2-dimensionalnuclear Overhauser effect (NOE) experiment. ¹H NMR (300 MHz, DMSO-d₆) δ7.81 (d, J=1.3 Hz, 1H), 7.65 (m, 2H), 7.41 (d, J=1.3 Hz, 1H), 7.32 (dd,J=1.3, 8.1 Hz, 1H), 5.27 (s, 2H), 2.76 (s, 3H). LCMS (ESI) m/z 324 and326 (M+H)⁺.

Step 2:6-((4-Bromo-1H-imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazolewas synthesized as a white foam (443 mg) using a procedure analogous tothat described in Step 6 of Example 36, substituting6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylthio)benzo[d]oxazole fromStep 1 of this Example for6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole usedin Example 36. LCMS (ESI) m/z 340 and 342 (M+H)⁺.

Step 3:(1R,2R)-2-((6-((4-Bromo-1H-imidazol-1-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanolwas synthesized as an orange solid (280 mg, 96%) using a procedureanalogous to that described in Step 7 of Example 36, substituting6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazolefrom Step 2 of this Example for6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazoleused in Example 36. LCMS (ESI) m/z 392 and 394 (M+H)⁺.

Step 4:(1R,2R)-2-((6-((4-(1-Methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanolwas synthesized as a white powder (27 mg, 10%) using a procedureanalogous to that described in Step 8 of Example 36, substituting(1R,2R)-2-((6-((4-bromo-1H-imidazol-1-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanolfrom Step 3 of this Example for(1R,2R)-2-((6-((4-bromo-1H-imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolused in Example 36. ¹H NMR (300 MHz, DMSO-d₆) δ 7.78-7.86 (m, 2H), 7.75(s, 1H), 7.57 (s, 1H), 7.32 (s, 1H), 7.26 (s, 1H), 7.17 (m, 1H), 7.09(m, 1H), 5.15 (s, 2H), 4.71 (d, J=4.3 Hz, 1H), 3.80 (s, 3H), 3.27-3.42(m, 2H), 1.81-2.03 (m, 2H), 1.55-1.70 (m, 2H), 1.10-1.34 (m, 4H). LCMS(ESI) m/z 393 (M+H)⁺.

Example 78 Preparation of(1R,2R)-2-((6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: To a stirred mixture of 6-bromo-3-nitro-2-pyridinamine (2.5 g,11.47 mmol) in a mixture of glacial HOAc (10 mL), MeOH (10 mL) and EtOH(10 mL) at 0° C. was added portionwise zinc dust (3.73 g, 57.35 mmol).The mixture was stirred at rt for 15 h. The mixture was filtered throughCelite, and the filtrate was concentrated under reduced pressure. Theresidue was partitioned between saturated aq NaHCO₃ and EtOAc. Theorganic layer was separated and the aqueous layer was extracted withadditional EtOAc. The combined organic layers were washed with brine,separated and dried over MgSO₄, filtered, and concentrated under reducedpressure to afford 6-bromopyridine-2,3-diamine (1.30 g, 60%) as a solidthat did not require further purification. ¹H NMR (300 MHz, DMSO-d₆) δ6.61 (d, J=7.7 Hz, 1H), 6.47 (d, J=7.7 Hz, 1H), 5.82 (s, 2H), 4.79 (s,2H). LCMS (ESI) m/z 188 and 190 (M+H)⁺.

Step 2: A stirred mixture of 6-bromopyridine-2,3-diamine (1.30 g, 6.91mmol) from Step 1 of this Example, formic acid (0.7 mL), andtriethylorthoformate (28 mL) was heated at 100° C. for 1.5 h. After thereaction mixture was cooled to rt, the mixture was concentrated underreduced pressure. The residue was triturated with a mixture of 5% MeOHin DCM. The solid was collected by filtration and dried to afford5-bromo-3H-imidazo[4,5-b]pyridine (245 mg, 18%) as a tan solid which didnot require further purification. The filtrate was concentrated underreduced pressure, and the residue was purified by silica gel flashchromatography (eluting with 100% DCM to 10% MeOH in DCM) to affordadditional 5-bromo-3H-imidazo[4,5-b]pyridine (756 mg, 55%) as a tansolid. ¹H NMR (300 MHz, DMSO-d₆) δ 13.08 (br s, 1H), 8.50 (s, 1H), 8.00(d, J=8.3 Hz, 1H), 7.43 (d, J=8.3 Hz, 1H). LCMS (ESI) m/z 198 and 200(M+H)⁺.

Step 3: To a stirred solution of 5-bromo-3H-imidazo[4,5-b]pyridine (1 g,5.05 mmol) from Step 2 of this Example in anhydrous DMF (25 mL) at 0° C.was added in one portion sodium hydride (60% dispersion in mineral oil,222 mg 5.56 mmol), and the mixture was stirred at 0° C. for 30 min. Tothe reaction mixture was added a solution of6-(chloromethyl)-2-(methylthio)benzo[d]thiazole (1.39 g, 6.06 mmol) fromStep 4 of Example 36 in DMF (5 mL). The mixture was allowed to warm tort and stirred for a further 15 h. To the reaction mixture was addedwater (300 mL) and the mixture was extracted with EtOAc (3×50 mL). Thecombined organic layers were washed with water and then brine. Theorganic layer was separated, dried over MgSO₄, filtered, andconcentrated under reduced pressure. The residue was purified by silicagel flash chromatography eluting with 100% DCM, followed by 1% MeOH inDCM to afford6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole(1.02 g, 52%) as a white solid. The regiochemistry of the alkylation wasdetermined by 2-dimensional nuclear Overhauser effect (NOE) experiment.¹H NMR (300 MHz, DMSO-d₆) δ 8.65 (s, 1H), 8.09 (d, J=8.3 Hz, 1H), 7.96(d, J=0.9 Hz, 1H), 7.83 (d, J=8.3 Hz, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.43(dd, J=1.5, 8.3 Hz, 1H), 5.60 (s, 2H), 2.77 (s, 3H). LCMS (ESI) m/z 391and 393 (M+H)⁺.

Step 4: To a stirred solution of6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole(1.02 g, 2.61 mmol) from Step 3 of this Example in DCM (50 mL) at 0° C.was added 70% meta-chloroperbenzoic acid (707 mg, 2.87 mmol) and themixture was allowed to warm to rt and stirred for a further 45 min. Tothe mixture was added saturated aq NaHCO₃ and the organic layer wasseparated. The aqueous layer was extracted with DCM and the combinedorganic layers were washed with saturated aq NaHCO₃. The organic layerwas separated, dried over MgSO₄, filtered, and the filtrate wasconcentrated under reduced pressure to afford6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole(1.06 g, 100%) as a cream solid which did not require furtherpurification. ¹H NMR (300 MHz, DMSO-d₆) δ 8.68 (s, 1H), 8.18 (s, 1H),8.08-8.12 (m, 2H), 7.61 (m, 1H), 7.50 (d, J=9 Hz, 1H), 5.68 (s, 2H),3.07 (s, 3H); LCMS (ESI) m/z 407 and 409 (M+H)⁺.

Step 5: A stirred mixture of6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole(50 mg, 0.123 mmol) from Step 4 of this Example,(1R,2R)-(−)-2-aminocyclohexanol (42 mg, 0.369 mmol), and DIEA (46 mg,0.369 mmol) in anhydrous DMA (1 mL) was heated in a sealed vessel at100° C. for 15 h. The reaction was allowed to cool to rt and then waspurified directly by reverse-phase HPLC using a mixture of water (5%CH₃CN, 0.05% HOAc) and CH₃CN (0.05% HOAc) as the mobile phase and VarianPursuit XRs diphenyl column as the stationary phase to afford(1R,2R)-2-((6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(12 mg, 21%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.60 (s, 1H),7.98-8.10 (m, 2H), 7.64 (d, J=1.1 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.31(m, 1H), 7.18 (dd, J=1.6, 8.2 Hz, 1H), 5.46 (s, 2H), 4.79 (br s, 1H),3.50 (m, 1H), 3.30 (m, 1H), 2.04 (m, 1H), 1.87 (m, 1H), 1.65-1.67 (m,2H), 1.12-1.34 (m, 4H). LCMS (ESI) m/z 458 and 460 (M+H)⁺.

Example 79 Preparation of methyl3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate

Step 1: To a stirred mixture of methyl 6-amino-5-nitronicotinate (2 g,10.15 mmol) in a mixture of THF (30 mL) and MeOH (10 mL) at rt was addedpalladium (10 wt % on activated carbon, 100 mg), and the mixture stirredunder hydrogen gas (1 atmosphere) for 15 h. The mixture was filteredthrough Celite, and the filtrate was concentrated under reduced pressureto afford methyl 5,6-diaminonicotinate (1.69 g, 100%) as a yellow solidwhich did not require further purification. ¹H NMR (300 MHz, DMSO-d₆) δ7.94 (d, J=2.1 Hz, 1H), 7.16 (d, J=2.1 Hz, 1H), 6.27 (br s, 2H), 4.92(br s, 2H), 3.74 (s, 3H). LCMS (ESI) m/z 168 (M+H)⁺.

Step 2: A stirred mixture of methyl 5,6-diaminonicotinate (1.69 g, 10.12mmol) from Step 1 of this Example, formic acid (0.5 mL), andtriethylorthoformate (25 mL) was heated at 90° C. for 2.5 h. Thereaction mixture was cooled to rt and then the precipitated solid wascollected by filtration and dried to afford methyl3H-imidazo[4,5-b]pyridine-6-carboxylate (588 mg, 33%) as a cream solidwhich did not require further purification. The filtrate wasconcentrated under reduced pressure, and the residue purified by silicagel flash chromatography eluting with 100% DCM to 10% MeOH in DCM toafford additional methyl 3H-imidazo[4,5-b]pyridine-6-carboxylate (550mg, 31%) as a cream solid. ¹H NMR (300 MHz, DMSO-d₆) δ 13.33 (br s, 1H),8.95 (d, J=1.5 Hz, 1H), 8.64 (s, 1H), 8.50 (d, J=1.5 Hz, 1H), 3.91 (s,3H). LCMS (ESI) m/z 178 (M+H)⁺.

Step 3: To a stirred solution of methyl3H-imidazo[4,5-b]pyridine-6-carboxylate (1.34 g, 7.56 mmol) from Step 2of this Example in anhydrous DMF (25 mL) at 0° C. was added in oneportion sodium hydride (60% dispersion in mineral oil, 333 mg, 8.32mmol) and the mixture was stirred at 0° C. for 30 min. To the reactionmixture was added a solution of6-(chloromethyl)-2-(methylthio)benzo[d]thiazole (1.3 g, 5.66 mmol) fromStep 4 of Example 36 in DMF (5 mL). The mixture was allowed to warm tort then stirred for a further 15 h. To the reaction mixture was addedwater (300 mL) and the mixture was extracted with EtOAc (3×50 mL). Thecombined organic layers were washed with water and then brine, driedover MgSO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by silica gel flash chromatography eluting with100% DCM followed by 1% MeOH in DCM to afford methyl3-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate(1.3 g, 46%) as a white solid. The regiochemistry of the alkylation wasdetermined by 2-dimensional nuclear Overhauser effect (NOE) experiment.¹H NMR (300 MHz, DMSO-d₆) δ 8.95 (d, J=1.9 Hz, 1H), 8.81 (s, 1H), 8.56(d, J=1.7 Hz, 1H), 8.00 (d, J=1.1 Hz, 1H), 7.80 (d, J=8.5 Hz, 1H), 7.47(dd, J=1.6, 8.4 Hz, 1H), 5.66 (s, 2H), 3.90 (s, 3H), 2.76 (s, 3H). LCMS(ESI) m/z 371 (M+H)⁺.

Step 4: To a stirred solution of methyl3-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate(300 mg, 0.811 mmol) from Step 3 of this Example in DCM (10 mL) at 0° C.was added 70% meta-chloroperbenzoic acid (154 mg, 0.892 mmol) and themixture was allowed to warm to rt and stirred for a further 4 h. To themixture was added saturated aq NaHCO₃ and the organic layer wasseparated. The aqueous layer was extracted with DCM and the combinedorganic layers were washed with saturated aq NaHCO₃. The organic layerwas separated, dried over MgSO₄, filtered, and concentrated underreduced pressure to afford 370 mg of a 2:1 mixture of methyl3-((2-(methylsulfinyl)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylateand methyl3-((2-(methylsulfonyl)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylateas an oil that was not purified further. LCMS (ESI) m/z 387 (M+H)⁺(consistent with methyl3-((2-(methylsulfinyl)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate)and m/z 403 (M+H)⁺ (consistent with methyl3-((2-(methylsulfonyl)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate).

Step 5: A 2:1 mixture of methyl3-((2-(methylsulfinyl)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylateand methyl3-((2-(methylsulfonyl)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate(360 mg) from Step 4 of this Example was dissolved in anhydrous DMA (10mL), and (1R,2R)-(−)-2-aminocyclohexanol (322 mg, 2.79 mmol) and DIEA(360 mg, 2.79 mmol) were added. The reaction vessel was sealed and themixture was heated with stirring at 100° C. for 19 h. LCMS indicated thereaction was not complete. To the reaction mixture was added additional(1R,2R)-(−)-2-aminocyclohexanol (100 mg, 0.870 mmol) and the reactionvessel was sealed and the mixture was heated at 100° C. for a further 15h. After the reaction mixture was cooled to rt, one half of the reactionmixture was purified directly by reverse-phase HPLC using a mixture ofwater (5% CH₃CN, 0.05% HOAc) and CH₃CN (0.05% HOAc) as the mobile phaseand Varian Pursuit XRs diphenyl column as the stationary phase to affordmethyl3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate(19 mg) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.96 (d, J=7.3 Hz,1H), 8.76 (m, 1H), 8.54 (m, 1H), 7.99 (br s, 1H), 7.66 (d, J=7.2 Hz,1H), 7.16-7.33 (m, 2H), 5.51 (br s, 2H), 4.76 (br s, 1H), 3.89 (s, 3H),3.30-3.50 (m, 2H), 2.02 (m, 1H), 1.86 (m, 1H), 1.50-1.70 (m, 2H),1.10-1.30 (m, 4H). LCMS (ESI) m/z 438 (M+H)⁺.

Example 80 Preparation of(1R,2R)-1-((6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol

A stirred mixture of6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole(130 mg, 0.332 mmol) from Step 4 of Example 78,(1R,2R)-(−)-trans-1-amino-2-indanol (198 mg, 1.33 mmol), and DIEA (214mg, 1.66 mmol) in anhydrous DMA (2 mL) in a sealed reaction vessel washeated in a Biotage microwave synthesizer at 140° C. for 1.5 h. LCMSindicated that the reaction was incomplete. Additional(1R,2R)-(−)-trans-1-amino-2-indanol (50 mg, 0.335 mmol) was added, andthe mixture was heated in a Biotage microwave synthesizer at 140° C. fora further 45 min. The reaction mixture was cooled to rt and purifieddirectly by reverse-phase HPLC using a mixture of water (5% CH₃CN, 0.05%HOAc) and CH₃CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRsdiphenyl column as the stationary phase to afford(1R,2R)-1-((6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol(24 mg, 15%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.62 (s, 1H),8.47 (d, J=7.9 Hz, 1H), 8.08 (d, J=8.3 Hz, 1H), 7.69 (s, 1H), 7.49 (d,J=8.3 Hz, 1H), 7.37 (d, J=8.3 Hz, 1H), 7.11-7.28 (m, 5H), 5.45-5.54 (m,3H), 5.18 (t, J=7.1 Hz, 1H), 4.24-4.35 (m, 1H), 3.16 (dd, J=6.9, 15.5Hz, 1H), 2.74 (dd, J=7.1, 15.5 Hz, 1H). LCMS (ESI) m/z 492 and 494(M+H)⁺.

Example 81 Preparation of3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylicacid

A mixture of methyl3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate(210 mg, 0.48 mmol) from Example 79 in THF (5 mL) and 1 M aq LiOH (5 mL)was stirred at rt for 3 h. The reaction mixture was acidified to pH˜1.0with 2 M aq HCl, and the mixture was purified directly by reverse-phaseHPLC using a mixture of water (5% CH₃CN, 0.05% HOAc) and CH₃CN (0.05%HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as thestationary phase to afford3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylicacid (37 mg, 18%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 13.15(br s, 1H), 8.96 (d, J=1.7 Hz, 1H), 8.74 (s, 1H), 8.52 (d, J=1.9 Hz,1H), 7.98 (d, J=7.3 Hz, 1H), 7.67 (d, J=1.1 Hz, 1H), 7.19-7.33 (m, 2H),5.53 (s, 2H), 4.75 (br s, 1H), 3.51 (m, 1H), 3.33 (m, 1H), 2.03 (m, 1H),1.87 (m, 1H), 1.55-1.68 (m, 2H), 1.09-1.35 (m, 4H). LCMS (ESI) m/z 424(M+H)⁺.

Example 82 Preparation of(1R,2R)-2-((6-((6-(morpholinomethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

A stirred mixture of(1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(100 mg, 0.22 mmol) from Example 29, potassium(morpholin-4-yl)methyltrifluoroborate (59 mg, 0.28 mmol), Pd(OAc)₂ (1.5mg, 0.007 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl(6.2 mg, 0.013 mmol) and Cs₂CO₃ (213 mg, 0.66 mmol) in THF/H₂O (1.5 mL,4:1, v/v) was purged with argon for 10 min. The mixture was then heatedat 85° C. in a sealed reaction vessel overnight. LCMS showed thereaction complete. After cooling to rt, the reaction mixture wasfiltered through a Celite plug and the filtrate was purified byreverse-phase preparative HPLC using a mixture of water (5% CH₃CN, 0.05%HCOOH) and CH₃CN (0.05% HCOOH) as the mobile phase and Varian PursuitXRs C18 column as the stationary phase to afford(1R,2R)-2-((6-((6-(morpholinomethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolas a white powder (36 mg, 35%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.57 (s,1H), 8.31 (d, J=1.5 Hz, 1H), 7.88-8.04 (m, 2H), 7.67 (d, J=0.9 Hz, 1H),7.26-7.33 (m, 1H), 7.17-7.26 (m, 1H), 5.46 (s, 2H), 4.75 (br s, 1H),3.60 (s, 2H), 3.45-3.58 (m, 5H), 2.36 (br s, 4H), 2.03 (d, J=10.4 Hz,1H), 1.79-1.89 (m, 1H), 1.62 (d, J=5.1 Hz, 2H), 1.05-1.37 (m, 4H). LCMS(ESI) m/z 479 (M+H)⁺.

Example 83 Preparation of either(1R,2R)-1-((6-((4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-olor(1R,2R)-1-((6-((5-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-olAlternative to Product of Example 32

Step 1:6-((5-(1-Methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole or6-((4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazolewas synthesized as a white foam (140 mg) using a procedure analogous tothat described in Step 5 of Example 32, substituting regioisomer 2 fromStep 4 of Example 32, (either6-((5-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazoleor6-((4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole)for regioisomer 1, used in Example 32. LCMS (ESI) m/z 356 (M+H)⁺.

Step 2:(1R,2R)-1-((6-((4-(1-Methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-olor(1R,2R)-1-((6-((5-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol(alternative of starting material in Step 6 of Example 32) wassynthesized as a white powder (10 mg, 8%) using a procedure analogous tothat described in Step 6 of Example 32, substituting the product fromStep 1 of this Example for6-((5-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole or6-((4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole used in Example 32. ¹H NMR (300 MHz, DMSO-d₆)δ 8.50 (d, J=7.9 Hz, 1H), 7.81 (s, 1H), 7.73 (d, J=0.9 Hz, 1H), 7.66 (s,1H), 7.58 (s, 1H), 7.38 (d, J=8.3 Hz, 1H), 7.11-7.30 (m, 6H), 5.54 (m,1H), 5.11-5.25 (m, 3H), 4.31 (m, 1H), 3.81 (s, 3H), 3.17 (m, 1H), 2.75(m, 1H). LCMS (ESI) m/z 443 (M+H)⁺.

Example 84 Preparation of(1R,2R)-2-((6-((6-(hydroxymethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

To a stirred mixture of methyl3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate(76 mg, 0.174 mmol) from Example 79 in anhydrous DCM (1 mL) at −50° C.under argon was added dropwise diisobutylaluminum hydride (1 M solutionin DCM, 0.696 μL, 696 mmol). The mixture was allowed to warm to −20° C.and stirred for 10 min. The reaction mixture was acidified to pH˜1.0with 2 M aq HCl, and the mixture was purified directly by reverse-phaseHPLC using a mixture of water (5% CH₃CN, 0.05% HOAc) and CH₃CN (0.05%HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as thestationary phase to afford(1R,2R)-2-((6-((6-(hydroxymethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(20 mg, 28%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.56 (s, 1H),8.35 (d, J=1.3 Hz, 1H), 7.93-8.01 (m, 2H), 7.65 (s, 1H), 7.28 (m, 1H),7.20 (m, 1H), 5.47 (s, 2H), 5.29 (br s, 1H), 4.75 (d, J=4.0 Hz, 1H),4.62 (br s, 2H), 3.50 (m, 1H), 3.30 (m, 1H), 2.03 (m, 1H), 1.87 (m, 1H),1.55-1.65 (m, 2H), 1.10-1.35 (m, 4H). LCMS (ESI) m/z 410 (M+H)⁺.

Example 85 Preparation of(1R,2R)-2-((6-((6-(methylthio)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

(1R,2R)-2-((6-((6-(Methylthio)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(25 mg, 18%) was obtained as a tan powder using a procedure analogous tothat described in Example 82, substituting potassium(thiomethyl)methyltrifluoroborate for potassium(morpholin-4-yl)methyltrifluoroborate, substituting dioxane/H₂O forTHF/H₂O used in Example 82, and running the reaction at 100° C. insteadof 85° C. ¹H NMR (300 MHz, MeOH-d₄) δ 8.37-8.50 (m, 2H), 8.07 (d, J=1.7Hz, 1H), 7.64 (s, 1H), 7.34-7.40 (m, 1H), 7.25-7.34 (m, 1H), 5.53 (s,2H), 3.58 (dd, J=3.4, 9.8 Hz, 1H), 3.39-3.51 (m, 1H), 2.56 (s, 3H),2.10-2.24 (m, 1H), 2.03 (d, J=10.9 Hz, 1H), 1.64-1.85 (m, 2H), 1.13-1.51(m, 4H). LCMS (ESI) m/z 426 (M+H)⁺.

Example 86 Preparation of(1R,2R)-2-((6-((6-((methylthio)methyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

(1R,2R)-2-((6-((6-((methylthio)methyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(5 mg, 4%) was obtained as a tan powder using a procedure analogous tothat described in Example 82, substituting potassium(thiomethyl)methyltrifluoroborate for potassium(morpholin-4-yl)methyltrifluoroborate used in Example 82, substitutingdioxane/H₂O for THF/H₂O used in Example 82, and running the reaction at100° C. instead of 85° C. ¹H NMR (300 MHz, MeOH-d₄) δ 8.29 (s, 2H), 7.95(br s, 1H), 7.52 (s, 1H), 7.22-7.30 (m, 1H), 7.13-7.22 (m, 1H), 5.43 (s,2H), 3.76 (s, 2H), 3.47 (dd, J=3.4, 9.8 Hz, 1H), 3.27-3.40 (m, 1H), 2.04(d, J=11.7 Hz, 1H), 1.93 (br s, 1H), 1.90 (s, 3H), 1.52-1.74 (m, 2H),1.01-1.40 (m, 4H). LCMS (ESI) m/z 440 (M+H)⁺.

Example 87 Preparation of3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile

A stirred mixture of(1R,2R)-2-((6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(100 mg, 0.218 mmol) from Example 78, zinc cyanide (77 mg, 0.654 mmol),and 1,1′-bis(diphenylphosphino)ferrocene (18 mg, 0.0327 mmol) inanhydrous DMF (2 mL) at rt was purged for 15 min with a stream of argon.To the resulting mixture was added tris(dibenzylideneacetone)dipalladium (18 mg, 0.0218 mmol). The reaction vessel was sealed and themixture was stirred at 100° C. for 2 h. After cooling to rt, thereaction mixture was purified directly by reverse-phase HPLC using amixture of water (5% CH₃CN, 0.05% HOAc) and CH₃CN (0.05% HOAc) as themobile phase and Varian Pursuit XRs diphenyl column as the stationaryphase to afford3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile(34 mg, 39%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.91 (s, 1H),8.34 (d, J=8.3 Hz, 1H), 8.01 (d, J=7.3 Hz, 1H), 7.92 (d, J=8.1 Hz, 1H),7.67 (d, J=1.1 Hz, 1H), 7.32 (m, 1H), 7.22 (m, 1H), 5.53 (s, 2H), 4.77(br s, 1H), 3.51 (m, 1H), 3.30 (m, 1H), 2.03 (m, 1H), 1.85 (m, 1H),1.65-1.67 (m, 2H), 1.08-1.37 (m, 4H). LCMS (ESI) m/z 405 (M+H)⁺.

Example 88 Preparation of1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)ethanone

A stirred mixture of(1R,2R)-2-((6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(100 mg, 0.218 mmol) from Example 78, tributyl(1-ethoxyvinyl)tin (157mg, 0.436 mmol) in anhydrous DMF (2 mL) at rt was purged for 15 min witha stream of argon. To the resulting mixture was addedtetrakis(triphenylphosphine) palladium (0) (38 mg, 0.0327 mmol). Thereaction vessel was sealed and the mixture was stirred at 110° C. for 2h. After cooling to rt, 2 M aq HCl (0.5 mL) was added, and the mixturewas stirred at rt for 1.5 h. The mixture was purified directly byreverse-phase HPLC using a mixture of water (5% CH₃CN, 0.05% HOAc) andCH₃CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenylcolumn as the stationary phase to afford crude1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)ethanone.The crude product was triturated with Et₂O and the solid was collectedby filtration and dried to afford1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)ethanone(19 mg, 21%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.84 (s, 1H),8.22 (d, J=8.5 Hz, 1H), 8.00 (d, J=7.5 Hz, 1H), 7.92 (d, J=8.3 Hz, 1H),7.80 (s, 1H), 7.26-7.39 (m, 2H), 5.55 (s, 2H), 4.77 (d, J=4.9 Hz, 1H),3.50 (m, 1H), 3.30 (m, 1H), 2.74 (s, 3H), 2.02 (m, 1H), 1.87 (m, 1H),1.55-1.67 (m, 2H), 1.12-1.32 (m, 4H). LCMS (ESI) m/z 422 (M+H)⁺.

Example 89 Preparation of3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-N-methyl-3H-imidazo[4,5-b]pyridine-6-carboxamide

To a stirred mixture of3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylicacid (70 mg, 0.165 mmol) from Example 81 and TEA (67 mg, 0.660 mmol) inanhydrous THF (2.5 mL) at rt was added methylamine (2 M solution in THF,413 μL, 0.825 mmol) followed bybenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(109 mg, 0.248 mmol). The mixture was stirred at rt for 4.5 h. Themixture was purified by reverse-phase HPLC using a mixture of water (5%CH₃CN, 0.05% HOAc) and CH₃CN (0.05% HOAc) as the mobile phase and VarianPursuit XRs diphenyl column as the stationary phase to afford3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-N-methyl-3H-imidazo[4,5-b]pyridine-6-carboxamide(26 mg, 36%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.86 (d,J=1.88 Hz, 1H), 8.69 (s, 1H), 8.59 (d, J=4.52 Hz, 1H), 8.49 (d, J=1.88Hz, 1H), 7.97 (d, J=7.54 Hz, 1H), 7.67 (d, J=1.13 Hz, 1H), 7.19-7.32 (m,2H), 5.51 (s, 2H), 4.73 (br. s., 1H), 3.51 (m, 1H), 3.30 (m, 1H), 2.82(d, J=4.33 Hz, 3H), 2.02 (m, 1H), 1.88 (m, 1H), 1.55-1.65 (m 2H),1.10-1.30 (m, 4H). LCMS (ESI) m/z 437 (M+H)⁺.

Example 90 Preparation ofN-hydroxy-3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboximidamide

A stirred mixture of3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrilefrom Example 43 (55 mg, 0.14 mmol) and excess 50% NH₂OH in H₂O (300 μL)in EtOH (3 mL) was heated at 80° C. for 1 h. LCMS analysis showed thatthe reaction was complete. The crude product was purified by preparativeHPLC using a mixture of water (5% CH₃CN, 0.05% AcOH) and CH₃CN (0.05%AcOH) as the mobile phase and Varian Pursuit XRs Diphenyl column as thestationary phase to affordN-hydroxy-3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboximidamide(8 mg, 13%) as a tan powder. ¹H NMR (300 MHz, MeOH-d₄) δ 8.73 (d, J=1.7Hz, 1H), 8.50 (s, 1H), 8.29 (d, J=1.7 Hz, 1H), 7.63 (s, 1H), 7.32-7.39(m, 1H), 7.25-7.32 (m, 1H), 5.55 (s, 2H), 3.50-3.65 (m, 1H), 3.37-3.49(m, 1H), 2.13 (d, J=12.1 Hz, 1H), 2.02 (d, J=10.4 Hz, 1H), 1.62-1.82 (m,2H), 1.15-1.49 (m, 4H). LCMS (ESI) m/z 438 (M+H)⁺.

Example 91 Preparation of(1R,2R)-2-((6-((6-(aminomethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolacetate

To a stirred mixture of3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrilefrom Example 43 (85 mg, 0.21 mmol) in THF (3 mL) at 0° C. was addeddropwise LAH in diethyl ether (2.0 M, 0.4 mL, 0.4 mmol). The resultingmixture was stirred at rt for 1 h, before another 0.4 mL of 2.0 M LAH indiethyl ether was added. After stirring at rt overnight, the reactionmixture was treated with sequential addition of 61 μL of H₂O, 61 μL of10% NaOH, and 183 μL of H₂O. The resulting mixture was filtered througha Celite plug and concentrated under reduced pressure. The residue waspurified by preparative HPLC using a mixture of water (5% CH₃CN, 0.05%AcOH) and CH₃CN (0.05% AcOH) as the mobile phase and Varian Pursuit XRsDiphenyl column as the stationary phase to afford(1R,2R)-2-((6-((6-(aminomethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolacetate (4 mg, 5%) as a tan powder. ¹H NMR (300 MHz, MeOH-d₄) δ 8.54 (d,J=9.2 Hz, 2H), 8.19 (s, 1H), 7.63 (s, 1H), 7.19-7.42 (m, 2H), 5.56 (s,2H), 4.27 (s, 2H), 3.57 (d, J=9.6 Hz, 1H), 3.37-3.50 (m, 1H), 2.13 (d,J=11.3 Hz, 1H), 2.01 (br s, 1H), 1.92 (s, 3H), 1.62-1.81 (m, 2H),1.17-1.49 (m, 4H). LCMS (ESI) m/z 409 (M+H)⁺.

Example 92 Preparation of3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-N,N-dimethyl-3H-imidazo[4,5-b]pyridine-6-carboxamide

To a stirred mixture of3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylicacid (65 mg, 0.153 mmol) from Example 81 and TEA (77 mg, 0.767 mmol) ina mixture of anhydrous THF (1.5 mL) and anhydrous DMF (0.5 mL) at rt wasadded dimethylamine (2 M solution in MeOH, 383 μL, 0.767 mmol) followedby benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (102 mg, 0.230 mmol). The resulting mixture wasstirred at rt for 2 h. The mixture was purified directly byreverse-phase HPLC using a mixture of water (5% CH₃CN, 0.05% HOAc) andCH₃CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenylcolumn as the stationary phase to afford3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-N,N-dimethyl-3H-imidazo[4,5-b]pyridine-6-carboxamide(33 mg, 48%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.70 (s, 1H),8.45 (s, 1H), 8.16 (s, 1H), 7.96 (d, J=7.54 Hz, 1H), 7.68 (s, 1H),7.20-7.33 (m, 2H), 5.50 (s, 2H), 4.73 (d, J=4.90 Hz, 1H), 3.51 (m, 1H),3.30 (m, 1H), 2.99 (br. s., 6H), 2.02 (m, 1H), 1.87 (m, 1H), 1.55-1.65(m, 2H), 1.10-1.30 (m, 4H). LCMS (ESI) m/z 451 (M+H)⁺.

Example 93 Preparation of(1R,2R)-2-((6-((6-(2H-tetrazol-5-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

A stirred mixture of3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrilefrom Example 43 (120 mg, 0.30 mmol), NaN₃ (29 mg, 0.45 mmol) and NH₄Cl(24 mg, 0.45 mmol) in DMF (1.5 mL) was heated at 100° C. overnight. LCMSshowed the reaction mostly completed. A portion of the reaction mixture(˜⅓) was cooled to rt and purified by preparative HPLC using a mixtureof water (5% CH₃CN, 0.05% AcOH) and CH₃CN (0.05% AcOH) as the mobilephase and Varian Pursuit XRs Diphenyl column as the stationary phase toafford(1R,2R)-2-((6-((6-(2H-tetrazol-5-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(4 mg, 9%) as a white powder. ¹H NMR (300 MHz, MeOH-d₄) δ 9.13 (s, 1H),8.67 (s, 1H), 8.60 (s, 1H), 7.76 (dd, J=7.5, 10.9 Hz, 2H), 7.69 (s, 1H),5.60 (s, 2H), 3.56 (d, J=9.6 Hz, 1H), 3.37-3.50 (m, 1H), 1.92-2.21 (m,2H), 1.72 (d, J=8.9 Hz, 2H), 1.17-1.49 (m, 4H). LCMS (ESI) m/z 448(M+H)⁺.

Example 94 Preparation of(1R,2R)-2-((6-((6-(2-methyl-2H-tetrazol-5-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

To the remaining portion of the reaction mixture from Example 93 wereadded excess Cs₂CO₃ (300 mg) and excess MeI (200 L). The resultingmixture was heated at 90° C. for 4 h. LCMS showed that the reaction wasmostly completed. After cooling to rt, the mixture was purified bypreparative HPLC using a mixture of water (5% CH₃CN, 0.05% AcOH) andCH₃CN (0.05% AcOH) as the mobile phase and Varian Pursuit XRs Diphenylcolumn as the stationary phase to afford(1R,2R)-2-((6-((6-(2-methyl-2H-tetrazol-5-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(8 mg) as a white powder. The regiochemistry assignment of the compoundwas consistent with the result from a NMR Nuclear Overhauser Effect(NOE) experiment. ¹H NMR (300 MHz, MeOH-d₄) δ 9.17 (s, 1H), 8.69 (s,1H), 8.55 (s, 1H), 7.67 (s, 1H), 7.25-7.41 (m, 2H), 5.58 (s, 2H),4.36-4.51 (m, 3H), 3.57 (d, J=9.6 Hz, 1H), 3.36-3.49 (m, 1H), 2.13 (d,J=11.3 Hz, 1H), 2.01 (br s, 1H), 1.71 (d, J=10.0 Hz, 2H), 1.12-1.48 (m,4H). LCMS (ESI) m/z 462 (M+H)⁺.

Example 95 Preparation of(1R,2R)-1-((6-((9H-purin-9-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol

Step 1: 6-((9H-Purin-9-yl)methyl)-2-(methylthio)benzo[d]thiazole wassynthesized as a white solid (690 mg, 30%) using a procedure analogousto that described in Step 3 of Example 47, substituting 9H-purine for5-bromo-6-methoxy-1H-benzo[d]-imidazole used in Example 47. Theregiochemistry of the alkylation was determined by 2-dimensional nuclearOverhauser effect (NOE) experiment. ¹H NMR (300 MHz, DMSO-d₆) δ 9.19 (s,1H), 8.96 (s, 1H), 8.80 (s, 1H), 8.01 (d, J=0.9 Hz, 1H), 7.82 (d, J=8.3Hz, 1H), 7.49 (dd, J=1.5, 8.5 Hz, 1H), 5.64 (s, 2H), 2.77 (s, 3H). LCMS(ESI) m/z 314 (M+H)⁺.

Step 2: 6-((9H-Purin-9-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole wassynthesized as a white foam (473 mg) using a procedure analogous to thatdescribed in Step 6 of Example 36, substituting6-((9H-purin-9-yl)methyl)-2-(methylthio)benzo[d]thiazole from Step 1 ofthis Example for6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole usedin Example 36. LCMS (ESI) m/z 330 (M+H)⁺.

Step 3: To a mixture of6-((9H-purin-9-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (270 mg,0.8 mmol) from Step 2 of the this Example and(1R,2R)-1-amino-2,3-dihydro-1H-inden-2-ol (246 mg, 1.6 mmol) in NMP (1.5mL) was added DIEA (570 μL, 3.3 mmol). The reaction vessel was sealedand the mixture was heated at 150° C. in the Biotage microwave reactorfor 1.5 h. The mixture was purified by reverse-phase preparative HPLCusing a mixture of water (5% CH₃CN, 0.05% HCOOH) and CH₃CN (0.05% HCOOH)as the mobile phase and Varian Pursuit XRs C18 column as the stationaryphase to afford(1R,2R)-1-((6-((9H-purin-9-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol(71 mg, 21%) as a white powder. ¹H NMR (300 MHz, DMSO-d₆) δ 9.18 (s,1H), 8.97 (s, 1H), 8.77 (s, 1H), 8.47 (d, J=8.1 Hz, 1H), 7.74 (d, J=1.3Hz, 1H), 7.37 (m, 1H), 7.30 (m, 1H), 7.11-7.25 (m, 4H), 5.45-5.57 (m,3H), 5.18 (t, J=7.1 Hz, 1H), 4.28 (m, 1H), 3.16 (dd, J=6.9, 15.5 Hz,1H), 2.74 (m, 1H). LCMS (ESI) m/z 415 (M+H)⁺.

Example 96 Preparation of(1R,2R)-2-((6-((6-ethynyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: 6-Iodo-3H-imidazo[4,5-b]pyridine (3.78 g) was obtained using aprocedure analogous to that described in Step 7 of Example 23,substituting 5-iodopyridine-2,3-diamine for6-methoxy-N²-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyridine-2,3-diamineused in Example 23. LCMS (ESI) m/z 246 (M+H)⁺.

Step 2:(1R,2R)-2-((6-((6-Iodo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolwas obtained as an off-white solid using procedures analogous to

those described in Steps 4-5 of Example 3 and Step 5 of Example 2,sequentially, substituting 6-iodo-3H-imidazo[4,5-b]pyridine from Step 1of this Example for 3H-imidazo[4,5-b]pyridine used in Step 4 of Example3, and then making the analogous substitutions for the startingmaterials used in Step 5 of Example 3 and Step 5 of Example 2. LCMS(ESI) m/z 506 (M+H)⁺.

Step 3: To a stirred suspension of(1R,2R)-2-((6-((6-iodo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(152 mg, 0.30 mmol) from Step 2 of this Example in DMF (3 mL) were addedCuI (6 mg, 0.032 mmol) and PdCl₂(PPh₃)₂(11 mg, 0.015 mmol). The mixturewas purged with argon while ethynyltrimethylsilane (85 μL, 0.60 mmol)and TEA (127 μL, 0.90 mmol) were added sequentially. The resultingmixture was stirred at rt for 1 h. LCMS analysis showed that thereaction was complete. Water (30 mL) was added and the resulting darkbrown solid was collected by filtration and dried to give crude(1R,2R)-2-((6-((6-((trimethylsilyl)ethynyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(100 mg, 70%). LCMS (ESI) m/z 476 (M+H)⁺.

Step 4: To a stirred solution of(1R,2R)-2-((6-((6-((trimethylsilyl)ethynyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(100 mg, 0.21 mmol) from Step 3 of this Example in MeOH (5 mL) was addedexcess K₂CO₃ (150 mg). The resulting mixture was stirred at rt for 30min. LCMS analysis showed that the reaction was complete. The reactionmixture was filtered through a Celite plug and the filtrate was purifiedby preparative HPLC using a mixture of water (5% CH₃CN, 0.05% AcOH) andCH₃CN (0.05% AcOH) as the mobile phase and Varian Pursuit XRs Diphenylcolumn as the stationary phase to afford(1R,2R)-2-((6-((6-ethynyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolas a tan powder (40 mg, 47%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.69 (s, 1H),8.50 (d, J=1.5 Hz, 1H), 8.23 (d, J=1.7 Hz, 1H), 8.02 (d, J=6.6 Hz, 1H),7.66 (s, 1H), 7.26-7.34 (m, 1H), 7.15-7.26 (m, 1H), 5.49 (s, 2H), 4.29(s, 1H), 3.26-3.38 (m, 2H), 2.03 (d, J=10.4 Hz, 1H), 1.85 (br s, 1H),1.62 (d, J=4.7 Hz, 2H), 1.00-1.38 (m, 4H). LCMS (ESI) m/z 404 (M+H)⁺.

Example 97 Preparation of(1R,2R)-2-((6-((6-morpholino-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

To a stirred solution of(1R,2R)-2-((6-((6-iodo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolfrom Step 2 of Example 96 (150 mg, 0.30 mmol) in DMSO (3 mL) were addedmorpholine (156 μL, 1.78 mmol), CuI (23 mg, 0.12 mmol), L-proline (14mg, 0.12 mmol), and K₂CO₃ (123 mg, 0.89 mmol). The resulting mixture wasflushed with argon, the reaction vessel was sealed and the mixture washeated at 100° C. for 2 h, then at 110° C. for 2 h. LCMS analysis showedthat the reaction complete. The reaction mixture was cooled to rt,filtered through a Celite plug, and the filtrate was purified bypreparative HPLC using a mixture of water (5% CH₃CN, 0.05% AcOH) andCH₃CN (0.05% AcOH) as the mobile phase and Varian Pursuit XRs Diphenylcolumn as the stationary phase to afford(1R,2R)-2-((6-((6-morpholino-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(15 mg, 11%) as a tan powder. ¹H NMR (300 MHz, DMSO-d₆) δ 8.46 (s, 1H),8.22 (d, J=2.3 Hz, 1H), 8.03 (d, J=7.2 Hz, 1H), 7.63 (br s, 2H),7.24-7.34 (m, 1H), 7.14-7.22 (m, 1H), 5.42 (s, 2H), 3.70-3.83 (m, 4H),3.48-3.55 (m, 2H), 3.07-3.15 (m, 4H), 2.03 (d, J=10.2 Hz, 1H), 1.87 (d,J=9.6 Hz, 1H), 1.61 (br s, 2H), 1.22 (d, J=7.3 Hz, 4H). LCMS (ESI) m/z465 (M+H)⁺.

Example 98 Preparation of(1R,2R)-2-((6-((6-vinyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

To a stirred mixture of(1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(200 mg, 0.44 mmol) from Example 29 in n-PrOH were added potassiumvinyltrifluoroborate (117 mg, 0.88 mmol), PdCl₂(dppf)DCM (18 mg, 0.022mmol), and TEA (122 μL, 0.88 mmol). The resulting mixture was purgedwith argon for 5 min, the reaction vessel was sealed and the mixture washeated at 100° C. overnight. LCMS analysis showed that the reaction wascomplete. The reaction mixture was cooled to rt and purified byreverse-phase preparative HPLC using a mixture of water (5% CH₃CN, 0.05%HCOOH) and CH₃CN (0.05% HCOOH) as the mobile phase and Varian PursuitXRs C18 column as the stationary phase to afford(1R,2R)-2-((6-((6-vinyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolas a tan powder (40 mg, 23%). ¹H NMR (300 MHz, MeOH-d₄) δ 8.50 (d, J=1.7Hz, 1H), 8.43 (s, 1H), 8.15 (d, J=1.7 Hz, 1H), 7.63 (s, 1H), 7.32-7.41(m, 1H), 7.25-7.32 (m, 1H), 6.91 (dd, J=10.9, 17.7 Hz, 1H), 5.91 (d,J=17.5 Hz, 1H), 5.53 (s, 2H), 5.35 (d, J=11.1 Hz, 1H), 3.50-3.66 (m,1H), 3.37-3.49 (m, 1H), 2.14 (d, J=12.1 Hz, 1H), 2.01 (br s, 1H),1.63-1.82 (m, 2H), 1.13-1.50 (m, 4H). LCMS (ESI) m/z 406 (M+H)⁺.

Example 99 Preparation ofN-((3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)methyl)acetamide

To a stirred solution of(1R,2R)-2-((6-((6-(aminomethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(50 mg, 0.12 mmol) from Example 91 in DCM (2 mL) were added pyridine (40μL, 0.48 mmol) and AcC1 (27 μL, 0.36 mmol). The resulting mixture wasstirred at rt for 3 h before it was concentrated under reduced pressure.The residue was purified by reverse-phase preparative HPLC using amixture of water (5% CH₃CN, 0.05% HCOOH) and CH₃CN (0.05% HCOOH) as themobile phase and Varian Pursuit XRs C18 column as the stationary phaseto affordN-((3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)methyl)acetamide(45 mg, 82%) as a white powder. ¹H NMR (300 MHz, DMSO-d₆) δ 8.58 (s,1H), 8.40 (br s, 1H), 8.31 (s, 1H), 7.84-8.10 (m, 2H), 7.65 (s, 1H),7.24-7.41 (m, 1H), 7.10-7.24 (m, 1H), 5.47 (s, 2H), 4.37 (d, J=5.5 Hz,2H), 3.34 (d, J=8.7 Hz, 2H), 1.97-2.16 (m, 1H), 1.89 (br s, 1H), 1.86(s, 3H), 1.61 (br s, 2H), 0.99-1.39 (m, 4H). LCMS (ESI) m/z 451 (M+H)⁺.

Example 100 Preparation of(1R,2R)-2-((6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: To a stirred mixture of(2-(methylthio)benzo[d]thiazol-6-yl)methanol (958 mg, 4.5 mmol) fromStep 3 of Example 36 in CH₂Cl₂ (20 mL) at 0° C. under argon was addedDess-Martin periodinane (2.0 g, 5.0 mmol) portionwise. The mixture wasstirred for 1 h and then diluted with CH₂Cl₂ (100 mL). To this mixturewas added a 50/50 mixture of saturated aq sodium sulfite and saturatedaq sodium bicarbonate (40 mL). This mixture was stirred for 10 min andthen the CH₂Cl₂ layer was separated, washed with a saturated aq sodiumbicarbonate (50 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure to afford 2-(methylthio)benzo[d]thiazole-6-carbaldehyde(937 mg, 99%) as a white solid. LCMS (ESI) m/z 210 (M+H)⁺.

Step 2: To a stirred mixture of 4-bromo-2-nitroaniline (694 mg, 3.2mmol) in TFA (5 mL) at −15° C. under argon was added NaBH(OAc)₃ (1.1 g,5.3 mmol) portionwise. The mixture was stirred for 10 min. To thestirred mixture was added dropwise2-(methylthio)benzo[d]thiazole-6-carbaldehyde (735 mg, 3.5 mmol) fromStep 1 of this Example in CH₂Cl₂ (3 mL). The mixture was stirred for 1 hand then concentrated under reduced pressure. The residue was purifiedby silica gel flash chromatography eluting with a gradient of 100%hexanes to 100% EtOAc to afford4-bromo-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroaniline(1.0 g, 77%) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.84 (t,J=6.0 Hz, 1H), 8.19 (d, J=2.4 Hz, 1H), 7.98 (s, 1H), 7.81 (d, J=8.3 Hz,1H), 7.56 (dd, J=2.4, 9.3 Hz, 1H), 7.46 (d, J=8.3 Hz, 1H), 6.88 (d,J=9.2 Hz, 1H), 4.75 (d, J=6.0 Hz, 2H), 2.77 (s, 3H). LCMS (ESI) m/z 410and 412 (M+H)⁺.

Step 3:4-Bromo-N¹-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diaminewas synthesized as an oil (1 g) using a procedure analogous to thatdescribed in Step 2 of Example 41, substituting4-bromo-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroanilinefrom Step 2 of this Example for4-bromo-5-methoxy-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroanilineused in Example 41. LCMS (ESI) m/z 379 and 381 (M+H)⁺.

Step 4:6-((5-Bromo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazolewas synthesized as a white solid (630 mg, 57%) using a procedureanalogous to that described in Step 3 of Example 41, substituting4-bromo-N¹-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diaminefrom Step 3 of this Example for4-bromo-5-methoxy-N²-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamineused in Example 41. ¹H NMR (300 MHz, DMSO-d₆) δ 8.51 (s, 1H), 8.00 (s,1H), 7.75-7.91 (m, 2H), 7.54 (d, J=8.5 Hz, 1H), 7.33-7.45 (m, 2H), 5.62(s, 2H), 2.77 (s, 3H). LCMS (ESI) m/z 389 and 391 (M+H)⁺.

Step 5: 6-((5-Bromo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole was synthesized as a white foam (1.0 g) usinga procedure analogous to that described in Step 6 of Example 36,substituting6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazolefrom Step 4 of this Example for the6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole usedin Example 36. LCMS (ESI) m/z 405 and 407 (M+H)⁺.

Step 6:(1R,2R)-2-((6-((5-Bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolwas synthesized as a white powder (36 mg, 36%) using a procedureanalogous to that described in Step 7 of Example 36, substituting6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazolefrom Step 5 of this Example for6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazoleused in Example 36. ¹H NMR (300 MHz, DMSO-d₆) δ 8.46 (s, 1H), 8.00 (d,J=7.5 Hz, 1H), 7.85 (d, J=1.7 Hz, 1H), 7.64 (d, J=1.3 Hz, 1H), 7.54 (d,J=8.7 Hz, 1H), 7.25-7.39 (m, 2H), 7.18 (dd, J=1.5, 8.3 Hz, 1H), 5.47 (s,2H), 4.76 (m, 1H), 3.50 (m, 1H), 3.33 (m, 1H), 2.02 (m, 1H), 1.87 (m,1H), 1.55-1.65 (m, 2H), 1.12-1.32 (m, 4H). LCMS (ESI) m/z 456 and 458(M+H)⁺.

Example 101 Preparation ofN-(1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-imidazol-4-yl)acetamide

Step 1: To a mixture of the regioisomers4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole and5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (643 mg, 2.3mmol) from Step 1 of Example 32, acetamide (275 mg, 5.0 mmol), andCs₂CO₃ (1.5 g, 5 mmol) in 1,4-dioxane (7 mL) was addedN,N′-dimethylethylenediamine (500 μL, 5 mmol). Argon was bubbled intothe mixture for 5 min followed by the addition of CuI (221 mg, 1.1mmol). Argon was bubbled into the mixture for an additional 5 min. Thenthe reaction vessel was sealed and the mixture was heated at 100° C. for15 h. The mixture was cooled to rt, then partitioned between EtOAc (100mL) and water (50 mL). The EtOAc layer was separated, washed with brine,dried over Na₂SO₄, filtered, and concentrated under reduced pressure.The residue was purified by silica gel flash chromatography eluting witha gradient of 100% hexanes to 100% EtOAc to afford a mixture ofregioisomersN-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)acetamide andN-(1-((2-(trimethyl silyl)ethoxy)methyl)-1H-imidazol-5-yl)acetamide (170mg, 29%) as an oil. LCMS (ESI) m/z 256 (M+H)⁺.

Step 2: The mixture of regioisomersN-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)acetamide andN-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)acetamide (170mg, 0.7 mmol) from Step 1 of this Example was stirred in 70% TFA inCH₂Cl₂ (10 mL) at rt for 4 h. The mixture was concentrated under reducedpressure to afford N-(1H-imidazol-4-yl)acetamide (147 mg) as a yellowfilm which was used in the next step without further purification. LCMS(ESI) m/z 126 (M+H)⁺.

Step 3:N-(1-((2-(Methylthio)benzo[d]thiazol-6-yl)methyl)-1H-imidazol-4-yl)acetamidewas synthesized as a white solid (58 mg, 15%) using a procedureanalogous to that described in Step 5 of Example 36, substitutingN-(1H-imidazol-4-yl)acetamide from Step 2 of this Example for4-bromo-1H-imidazole used in Example 36. The regiochemistry of thealkylation was determined by 2-dimensional nuclear Overhauser effect(NOE) experiment. ¹H NMR (300 MHz, DMSO-d₆) δ 10.27 (s, 1H), 7.94 (s,1H), 7.83 (d, J=8.5 Hz, 1H), 7.60 (s, 1H), 7.38 (d, J=8.5 Hz, 1H), 7.20(s, 1H), 5.24 (s, 2H), 2.78 (s, 3H), 1.94 (s, 3H). LCMS (ESI) m/z 319(M+H)⁺.

Step 4:N-(1-((2-(Methylsulfinyl)benzo[d]thiazol-6-yl)methyl)-1H-imidazol-4-yl)acetamidewas synthesized as a white foam (106 mg) using a procedure analogous tothat described in Step 6 of Example 36, substitutingN-(1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-1H-imidazol-4-yl)acetamidefrom Step 3 of this Example for6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole usedin Example 36. LCMS (ESI) m/z 351 (M+H)⁺

Step 5:N-(1-((2-(((1R,2R)-2-Hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-imidazol-4-yl)acetamidewas synthesized as a white powder (4 mg) using a procedure analogous tothat described in Step 7 of Example 36, substitutingN-(1-((2-(methylsulfinyl)benzo[d]thiazol-6-yl)methyl)-1H-imidazol-4-yl)acetamidefrom Step 4 of this Example for6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazoleused in Example 36. The powder was further purified by preparative TLCeluting with 10% MeOH in CH₂Cl₂ to affordN-(1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-imidazol-4-yl)acetamide(2 mg, 2%) as a white solid. ¹H NMR (300 MHz, MeOH-d₄) δ 7.50 (s, 2H),7.35 (d, J=8.1 Hz, 1H), 7.12-7.25 (m, 2H), 5.13 (s, 2H), 3.60 (m, 1H),3.43 (m, 1H), 1.96-2.20 (m, 5H), 1.67-1.80 (m, 2H), 1.20-1.47 (m, 4H).LCMS (ESI) m/z 386 (M+H)⁺.

Example 102 Preparation of(1R,2R)-2-((6-((6-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

To a stirred solution of(1R,2R)-2-((6-((6-vinyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(20 mg, 0.049 mmol) from Example 98 in 1:1 MeOH/THF (2 mL) was addedRaney Ni (10 mg). The resulting mixture was stirred under a H₂ balloonat rt for 4 h. LCMS analysis showed that the reaction was complete. Thereaction mixture was filtered through a Celite plug and the filtrate waspurified with preparative TLC to give(1R,2R)-2-((6-((6-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(6 mg, 30%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.53 (br s, 1H), 8.26 (br s,1H), 7.95 (d, J=12.4 Hz, 2H), 7.66 (br s, 1H), 7.25-7.42 (m, 1H),7.06-7.25 (m, 1H), 5.45 (br s, 2H), 4.74 (d, J=4.5 Hz, 1H), 3.51 (br s,1H), 2.73 (d, J=7.2 Hz, 2H), 2.04 (br s, 1H), 1.86 (br s, 1H), 1.62 (brs, 2H), 1.23 (t, J=6.8 Hz, 7H). LCMS (ESI) m/z 408 (M+H)⁺.

Example 103 Preparation of1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3-(1-methyl-1H-pyrazol-4-yl)pyrazin-2(1H)-one

Step 1: To 2,3-dichloropyrazine (1.12 g, 7.52 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.56 g, 7.52 mmol), bis(triphenylphosphine)palladium(II) dichloride(270 mg, 0.38 mmol), and Na₂CO₃ (2.4 g, 22.56 mmol) in a pressure tubewere added 1,2-dimethoxyethane (15 mL) and water (2 mL). The flask wasevacuated and flushed with argon (3×) and then sealed and heated at 90°C. overnight. The mixture was concentrated under reduced pressure andpurified by silica gel chromatography eluting with 20-100% EtOAc/hexanesto afford 2-chloro-3-(1-methyl-1H-pyrazol-4-yl)pyrazine (780 mg, 53%).LCMS (ESI) m/z 195 (M+H)⁺.

Step 2: To 2-chloro-3-(1-methyl-1H-pyrazol-4-yl)pyrazine (200 mg, 1.03mmol) from Step 1 of this Example in DMSO (1.5 mL) and water (1.5 mL)was added KOH (890 mg, 15.4 mmol) and the mixture was heated at 80° C.for 3 h. The mixture was cooled and partitioned between EtOAc and 4 NHCl. The aqueous layer was concentrated under reduced pressure and thena mixture of MeOH and EtOH was added and the suspension was filteredthrough Celite. The filtrate was concentrated under reduced pressure andthen Et₂O was added and the mixture again concentrated under reducedpressure. The residue was triturated with DCM and filtered to affordcrude 3-(1-methyl-1H-pyrazol-4-yl)pyrazin-2(1H)-one (300 mg,quantitative) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.60 (s,1H), 8.18 (s, 1H), 7.24-7.39 (m, 2H), 3.91 (s, 3H).

Step 3: To 3-(1-methyl-1H-pyrazol-4-yl)pyrazin-2(1H)-one (139 mg, 0.78mmol) from Step 2 of this Example in DMF (3 mL) was added NaH (60% inmineral oil, 32 mg, 0.78 mmol) and the mixture was stirred at rt for 10min. 6-(Chloromethyl)-2-(methylthio)benzo[d]thiazole (180 mg, 0.78 mmol)from Step 4 of Example 36 was then added. The mixture was stirred at rtovernight and then concentrated under reduced pressure. The residue waspurified by silica gel chromatography eluting with 0-15% MeOH/DCM toafford impure3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyrazin-2(1H)-one(80 mg, 27%) which was used without further purification. LCMS (ESI) m/z370 (M+H)⁺.

Step 4: To3-(1-Methyl-1H-pyrazol-4-yl)-1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyrazin-2(1H)-one(80 mg, 0.21 mmol) from Step 3 of this Example in DCM (5 mL) at 0° C.was added 3-chloroperbenzoic acid (70%, 75 mg, 0.3 mmol) and the mixturewas stirred for 20 min. The mixture was diluted with DCM and then washedwith aq sodium thiosulfate and saturate

aq sodium bicarbonate. The organic layer was dried over sodium sulfateand concentrated under reduced pressure. To the residue was addedN,N-dimethylacetamide (4 mL), DIEA (0.075 mL, 0.43 mmol) and(1R,2R)-2-aminocyclohexanol (50 mg, 0.43 mmol). The mixture was heatedat 100° C. for 3 d and then purified by reverse-phase preparative HPLCusing a mixture of water (5% CH₃CN, 0.05% HCOOH) and CH₃CN (0.05% HCOOH)as the mobile phase and Varian Pursuit XRs C18 column as the stationaryphase to afford1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3-(1-methyl-1H-pyrazol-4-yl)pyrazin-2(1H)-one(7 mg, 8%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.55 (s, 1H), 8.09 (s, 1H), 8.00(d, J=7.54 Hz, 1H), 7.66-7.71 (m, 2H), 7.35 (d, J=4.33 Hz, 1H),7.29-7.33 (m, 1H), 7.22-7.27 (m, 1H), 5.14 (s, 2H), 4.77 (br. s., 1H),3.89 (s, 3H) 3.52 (br. s., 1H), 2.04 (d, J=10.36 Hz, 1H), 1.89 (br. s.,1H), 1.63 (br. s., 2H), 1.23 (d, J=5.84 Hz, 4H). LCMS (ESI) m/z 437(M+H)⁺.

Example 104 Preparation of(1R,2R)-2-((6-((6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

(1R,2R)-2-((6-((6-(3-Hydroxy-3-methylbut-1-yn-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(125 mg, 91%) was obtained as a white powder using a procedure analogousto that described in Step 3 of Example 96, substituting2-methylbut-3-yn-2-ol for ethynyltrimethylsilane used in Example 96. ¹HNMR (300 MHz, DMSO-d₆) δ 8.67 (br s, 1H), 8.41 (s, 1H), 8.10 (br s, 1H),7.99 (d, J=7.3 Hz, 1H), 7.66 (s, 1H), 7.26-7.36 (m, 1H), 7.17-7.26 (m,1H), 5.48 (s, 2H), 4.77 (br s, 1H), 3.48-3.61 (m, 2H), 2.03 (d, J=10.2Hz, 1H), 1.88 (d, J=10.0 Hz, 1H), 1.62 (d, J=4.5 Hz, 2H), 1.49 (s, 6H),1.22 (d, J=5.8 Hz, 4H). LCMS (ESI) m/z 462 (M+H)⁺.

Example 105 Preparation of(1R,2R)-2-((6-((2-(trifluoromethyl)-9H-purin-9-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: 2-(Trifluoromethyl)-9H-purine (940 mg, 94%) was obtained as awhite solid using a procedure analogous to that described in Step 7 ofExample 23, substituting 2-(trifluoromethyl)pyrimidine-4,5-diamine for6-methoxy-N²-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyridine-2,3-diamineused in Example 23. LCMS (ESI) m/z 189 (M+H)⁺.

Step 2:2-(Methylthio)-6-((2-(trifluoromethyl)-9H-purin-9-yl)methyl)benzo[d]thiazole(480 mg, 47%) was obtained as an oil using a procedure analogous to thatdescribed in Step 1 of Example 63, substituting2-(trifluoromethyl)-9H-purine from Step 1 of this Example for4-azabenzimidazole used in Example 63. LCMS (ESI) m/z 382 (M+H)⁺.

Step 3:(1R,2R)-2-((6-((2-(Trifluoromethyl)-9H-purin-9-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolwas obtained as a light brown solid using procedures analogous to thosedescribed in Step 5 of Example 3 followed by procedures analogous tothose used in Step 5 of Example 2, substituting2-(methylthio)-6-((2-(trifluoromethyl)-9H-purin-9-yl)methyl)benzo[d]thiazolefrom Step 2 of this Example for6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazoleused in Example 3, and substituting the product of that reaction for the2-bromo-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazoleused in Example 2. ¹H NMR (300 MHz, DMSO-d₆) δ 9.39 (s, 1H), 8.97 (s,1H), 8.05 (d, J=7.5 Hz, 1H), 7.69 (s, 1H), 7.29-7.39 (m, 1H), 7.14-7.28(m, 1H), 5.56 (s, 2H), 4.81 (br s, 1H), 3.50 (d, J=7.7 Hz, 2H),1.96-2.17 (m, 1H), 1.88 (d, J=9.6 Hz, 1H), 1.62 (br s, 2H), 0.93-1.41(m, 4H). LCMS (ESI) m/z 449 (M+H)⁺.

Example 106 Preparation of(1R,2R)-2-((6-((5-(methylsulfonyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

A stirred mixture of(1R,2R)-2-((6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(89 mg, 0.194 mmol) from Example 78, sodium methane sulfinate (80 mg,0.777 mmol), and N,N-dimethylethylenediamine (7 mg, 0.078 mmol) inanhydrous DMSO (2 mL) at rt was purged for 15 min with a stream ofargon. To the resulting mixture was added copper (I)trifluoromethane-sulfonate benzene complex (20 mg, 0.038 mmol). Thereaction vessel was sealed and the mixture was stirred at 125° C. for 5h. After cooling to rt, the reaction mixture was purified directly byreverse-phase HPLC using a mixture of water (5% CH₃CN, 0.05% HOAc) andCH₃CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenylcolumn as the stationary phase to afford(1R,2R)-2-((6-((5-(methylsulfonyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(33 mg, 37%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.91 (s, 1H),8.39 (d, J=8.3 Hz, 1H), 7.90-8.02 (m, 2H), 7.78 (s, 1H), 7.25-7.36 (m,2H), 5.54 (s, 2H), 4.74 (br s, 1H), 3.50 (br s, 1H), 3.33-3.34 (m, 4H),2.02 (m, 1H), 1.87 (m, 1H), 1.55-1.65 (m, 2H), 1.15-1.30 (m, 4H); LCMS(ESI) m/z 458 (M+H)⁺.

Example 107 Preparation of(1R,2R)-2-((6-((6-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: To a stirred mixture of(2-(methylthio)benzo[d]thiazol-6-yl)methanol (958 mg, 4.5 mmol) fromStep 3 of Example 36 in CH₂Cl₂ (20 mL) at 0° C. under argon was addedDess-Martin periodinane (2.1 g, 5.0 mmol) in small portions. After themixture was stirred for 1 hr at 0° C., it was diluted with CH₂Cl₂ (100mL) followed by the addition of a 1:1 mixture of saturated aq Na₂SO₃ andsaturated aq NaHCO₃ (40 mL). The mixture was stirred for 10 min. Thelayers were separated and the CH₂Cl₂ layer was sequentially washed withsaturated aq NaHCO₃ (50 mL) and brine (50 mL). The organic layer wasseparated and dried over Na₂SO₄, filtered, and concentrated underreduced pressure to yield 2-(methylthio)benzo[d]thiazole-6-carbaldehyde(937 mg, 99%) as an off white solid which did not require furtherpurification. ¹H NMR (300 MHz, DMSO-d₆) δ 10.06 (s, 1H), 8.62 (s, 1H),7.99 (s, 2H), 2.84 (s, 3H); LCMS (ESI) m/z 210 (M+H)⁺.

Step 2: To a stirred mixture of 5-bromo-2-nitroaniline (714 mg, 4.0mmol) in TFA (7 mL) at −15° C. under argon, was added NaBH(OAc)₃ (1.2 g,5.4 mmol) in small portions. The mixture was stirred for 15 min, then asolution of 2-(methylthio)benzo[d]thiazole-6-carbaldehyde in CH₂Cl₂ (2mL) was added dropwise. The mixture was stirred for 30 min thenconcentrated under reduced pressure to give a red oil. The oil waspartitioned between EtOAc (200 mL) and saturated aq NaHCO₃ (100 mL). Theorganic layer was separated and washed with brine (100 mL). The organiclayer was separated, dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by silica gel flashchromatography eluting with a gradient of 100% hexanes to 50% hexanes inEtOAc to afford5-bromo-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroaniline(1.1 g, 73%) as a yellow solid. LCMS (ESI) m/z 409, 411 (M+H)⁺.

Step 3:5-Bromo-N¹-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diaminewas synthesized as a brown solid (920 mg) using a procedure analogous tothat described in Step 2 of Example 41, substituting5-bromo-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroanilinefrom the previous step for4-bromo-5-methoxy-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroanilineused in Example 41. LCMS (ESI) m/z 379, 381 (M+H)⁺.

Step 4:6-((6-Bromo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazolewas synthesized as a yellow solid (701 mg, 70%) using a procedureanalogous to that described in Step 3 of Example 41, substituting5-bromo-N¹-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diaminefrom the previous step for4-bromo-5-methoxy-N¹-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamineused in Example 41. LCMS (ESI) m/z 389, 391 (M+H)⁺.

Step 5:6-((6-Bromo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazolewas synthesized as a yellow foam (811 mg) using a procedure analogous tothat described in Step 6 of Example 36, substituting6-((6-bromo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazolefrom the previous step for6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole usedin Example 36. LCMS (ESI) m/z 405, 407 (M+H)⁺.

Step 6:(1R,2R)-2-((6-((6-Bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolwas synthesized using a procedure analogous to that described in Step 7of Example 36, substituting6-((6-bromo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazolefrom the previous step for6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazoleused in Example 36. A portion of crude product was purified bypreparative HPLC using a mixture of water (5% CH₃CN, 0.05% HCOOH) andCH₃CN (0.05% HCOOH) as the mobile phase and a Varian Diphenyl column asthe stationary phase to yield(1R,2R)-2-((6-((6-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolas a white powder (33 mg)¹H NMR (300 MHz, DMSO-d₆) δ 8.44 (s, 1H), 8.00(d, J=7.5 Hz, 1H), 7.85 (d, J=1.5 Hz, 1H), 7.56-7.68 (m, 2H), 7.26-7.36(m, 2H), 7.15-7.24 (m, 1H), 5.47 (s, 2H), 4.76 (d, J=4.5 Hz, 1H), 3.52(m, 1H), 3.32 (m, 1H), 1.99 (m, 1H), 1.88 (m, 1H), 1.55-1.67 (m, 2H),1.12-1.30 (m, 4H); LCMS (ESI) m/z 456, 458 (M+H)⁺.

Example 108 Preparation of1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

Step 1:4-Bromo-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroanilinewas synthesized as a yellow solid (1.08 g, 77%) using a procedureanalogous to that described in Step 2 of Example 107, substituting4-bromo-2-nitroaniline for 5-bromo-2-nitroaniline used in Example 107.¹H NMR (300 MHz, DMSO-d₆) δ 8.84 (t, J=6.0 Hz, 1H), 8.19 (d, J=2.4 Hz,1H), 7.98 (s, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.56 (dd, J=2.4, 9.3 Hz, 1H),7.46 (d, J=8.3 Hz, 1H), 6.88 (d, J=9.2 Hz, 1H), 4.75 (d, J=6.0 Hz, 2H),2.77 (s, 3H); LCMS (ESI) m/z 410, 412 (M+H)⁺.

Step 2:4-Bromo-N¹-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diaminewas synthesized as a red oil using a procedure analogous to thatdescribed in Step 2 of Example 41, substituting4-bromo-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroanilinefrom the previous step for4-bromo-5-methoxy-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroanilineused in Example 41. LCMS (ESI) m/z 380, 382 (M+H)⁺.

Step 3:6-((5-Bromo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazolewas synthesized as a white solid (630 mg, 62% over two steps) using aprocedure analogous to that described in Step 3 of Example 41,substituting4-bromo-N¹-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diaminefrom the previous step for4-bromo-5-methoxy-N¹-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamineused in Example 41. ¹H NMR (300 MHz, DMSO-d₆) δ 8.51 (s, 1H), 8.00 (s,1H), 7.87 (d, J=1.7 Hz, 1H), 7.81 (d, J=8.5 Hz, 1H), 7.54 (d, J=8.5 Hz,1H), 7.33-7.45 (m, 2H), 5.62 (s, 2H), 2.77 (s, 3H); LCMS (ESI) m/z 390,392 (M+H)⁺.

Step 4: 6-((5-Bromo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole was synthesized as a white foam (830 mg) usinga procedure analogous to that described in Step 6 of Example 36,substituting6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazolefrom the previous step for6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole usedin Example 36. LCMS (ESI) m/z 405, 407 (M+H)⁺.

Step 5: To a suspension of6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (655 mg, 1.6 mmol) and(1R,2R)-2-aminocyclohexanol (558 mg, 4.8 mmol) in anhydrous DMA (3.0 mL)was added DIEA (842 μL, 4.8 mmol). The mixture was heated in a sealedtube at 110° C. for 18 h. The mixture was cooled to rt and addeddropwise to a stirred solution of water causing a precipitate to form.After stirring for 10 min, the solid was collected by filtration toafford(1R,2R)-2-((6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(837 mg) as a tan solid. The material was used in the next step withoutfurther purification. ¹H NMR (300 MHz, DMSO-d₆) δ 8.46 (s, 1H), 7.97 (d,J=7.5 Hz, 1H), 7.85 (d, J=1.7 Hz, 1H), 7.65 (s, 1H), 7.54 (d, J=8.5 Hz,1H), 7.26-7.39 (m, 2H), 7.19 (m, 1H), 5.47 (s, 2H), 4.74 (d, J=5.1 Hz,1H), 3.51 (m, 1H), 3.32 (m, 1H), 2.01 (m, 1H), 1.87 (m, 1H), 1.55-1.67(m, 2H), 1.13-1.32 (m, 4H); LCMS (ESI) m/z 457, 459 (M+H)⁺.

Step 6:1-((2-(((1R,2R)-2-Hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrilewas synthesized as a white powder (32 mg, 6%) using a procedureanalogous to that described in Step 1 of Example 53, substituting(1R,2R)-2-((6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolfrom the previous step for(1R,2R)-2-((6-((6-bromo-5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolused in Example 53. The product was further purified by silica gel flashchromatography eluting with 5% MeOH in CH₂Cl₂. ¹H NMR (300 MHz, DMSO-d₆)δ 8.66 (s, 1H), 8.22 (s, 1H), 7.98 (d, J=7.5 Hz, 1H), 7.79 (d, J=8.5 Hz,1H), 7.68 (s, 1H), 7.62 (m, 1H), 7.29 (m, 1H), 7.21 (m, 1H), 5.54 (s,2H), 4.73 (d, J=5.3 Hz, 1H), 3.51 (m, 1H), 3.33 (m, 1H), 2.03 (m, 1H),1.88 (m, 1H), 1.56-1.67 (m, 2H), 1.10-1.35 (m, 4H); LCMS (ESI) m/z 404(M+H)⁺.

Example 109 Preparation of(1R,2R)-2-((6-((6-(2-hydroxypropan-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: To a stirred solution of methyl3-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate(253 mg, 0.684 mmol) from Step 3 of Example 79 in a mixture of anhydrousDCM (2.5 mL) and anhydrous THF (6.4 mL) at 0° C. under an inertatmosphere was added dropwise methyl magnesium bromide (3M solution indiethyl ether, 0.49 mL, 1.47 mmol). The mixture was allowed to slowlywarm to rt and stir for 1.5 h. Additional methyl magnesium bromide (3Msolution in diethyl ether, 0.49 mL, 1.47 mmol) was added and the mixturewas stirred at rt for an additional 48 h. Additional methyl magnesiumbromide (3M solution in diethyl ether, 0.25 mL, 0.74 mmol) was added andthe mixture was stirred at rt for an additional 4 h. The reactionmixture was partitioned between EtOAc and a 1:1 mixture of saturated aqNH₄Cl and saturated aq NaHCO₃. The organic layer was separated, driedover MgSO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by silica gel flash chromatography eluting with100% DCM to 15% MeOH in DCM to afford2-(3-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)propan-2-ol(191 mg, 75%) as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.59 (s, 1H), 8.52(d, J=3.0 Hz, 1H), 8.12 (d, J=3.0 Hz, 1H), 8.00 (m, 1H), 7.81 (d, J=9.0Hz, 1H), 7.45 (dd, J=9.0, 3.0 Hz, 1H), 5.59 (s, 2H), 5.20 (s, 1H), 2.77(s, 3H), 1.51 (s, 6H); LCMS (ESI) m/z 371 (M+H)⁺.

Step 2:2-(3-((2-(Methylsulfinyl)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)propan-2-ol(140 mg, 70%) was obtained as a yellow solid using a procedure analogousto that described in Step 5 of Example 3, substituting2-(3-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)propan-2-olfrom Step 1 of this Example for6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazoleused in Example 3. LCMS (ESI) m/z 387 (M+H)⁺.

Step 3:(1R,2R)-2-((6-((6-(2-Hydroxypropan-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(17 mg, 11%) was obtained as a solid using a procedure analogous to thatdescribed in Step 5 of Example 70, substituting2-(3-((2-(methylsulfinyl)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)propan-2-olfrom Step 2 of this Example for6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazoleused in Example 70. ¹H NMR (300 MHz, DMSO-d₆) δ 8.54 (s, 1H), 8.53 (d,J=3.0 Hz, 1H), 8.10 (d, J=3.0 Hz, 1H), 7.97 (d, J=6.0 Hz, 1H), 7.66 (m,1H), 7.19-7.30 (m, 2H), 5.46 (s, 2H), 5.22 (br s, 1H), 4.76 (br d, J=3.0Hz, 1H), 3.50 (m, 1H), 3.30 (m, 1H), 2.03 (m, 1H), 1.86 (m, 1H),1.60-1.70 (m, 2H), 1.51 (s, 6H), 1.15-1.30 (m, 4H); LCMS (ESI) m/z 438(M+H)⁺.

Example 110 Preparation of1-(1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)ethanone

A stirred suspension of(1R,2R)-2-((6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(150 mg, 0.33 mmol) from Step 5 of Example 108 andtributyl(1-ethoxyvinyl)tin (177 mg, 0.5 mmol) in DMA (1.5 mL) was purgedwith a stream of argon for 5 min. To the mixture was addedtetrakis(triphenylphosphine)palladium (0) (57 mg, 0.05 mmol) and argonwas bubbled into the mixture for an additional 5 min. The reactionvessel was sealed and the mixture was heated at 110° C. for 3 h. Themixture was cooled to rt. To the mixture was added 0.5 M aq HCl (500 μL)followed by stirring at rt for 12 h. The mixture was filtered, and thefiltrate was purified directly by reverse-phase preparative HPLC using amixture of water (5% CH₃CN, 0.05% HCOOH) and CH₃CN (0.05% HCOOH) as themobile phase and a Varian Pursuit XRs C18 column as the stationaryphase. The product was further purified by silica gel flashchromatography eluting with 5% MeOH in CH₂Cl₂ to afford1-(1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)ethanone(11 mg, 8%) as a white powder. ¹H NMR (300 MHz, DMSO-d₆) δ 8.57 (s, 1H),8.32 (s, 1H), 7.97 (d, J=7.5 Hz, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.64-7.72(m, 2H), 7.30 (m, 1H), 7.20 (m, 1H), 5.52 (s, 2H), 4.73 (d, J=5.1 Hz,1H), 3.52 (m, 1H), 3.34 (m, 1H), 2.62 (s, 3H), 2.02 (m, 1H), 1.90 (m,1H), 1.55-1.69 (m, 2H), 1.10-1.35 (m, 4H); LCMS (ESI) m/z 421 (M+H)⁺.

Example 111 Preparation of1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

1-((2-(((1R,2R)-2-Hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrilewas synthesized as a white powder (23 mg, 13%) using a procedureanalogous to that described in Step 6 of Example 108, substituting(1R,2R)-2-((6-((6-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolfrom Step 6 of Example 107 for(1R,2R)-2-((6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolused in Example 108. ¹H NMR (300 MHz, DMSO-d₆) δ 8.70 (s, 1H), 8.27 (s,1H), 8.01 (d, J=7.3 Hz, 1H), 7.83 (d, J=8.3 Hz, 1H), 7.73 (s, 1H), 7.58(d, J=8.5 Hz, 1H), 7.23-7.35 (m, 2H), 5.53 (s, 2H), 4.76 (d, J=4.5 Hz,1H), 3.51 (m, 1H), 2.50 (m, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.55-1.67(m, 2H), 1.13-1.31 (m, 4H); LCMS (ESI) m/z 404 (M+H)⁺.

Example 112 Preparation of(1R,2R)-2-((6-((5-(methylsulfonyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

A stirred suspension of(1R,2R)-2-((6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(100 mg, 0.22 mmol) (prepared as described in Example 108, steps 1through 6), sodium methane sulfinate (89 mg, 0.9 mmol) andN,N-dimethylethylenediamine (9.6 μL, 0.9 mmol) was degassed under astream of argon for 5 min. Copper (I) trifluoromethane-sulfonate benzenecomplex (22 mg, 0.04 mmol) was added and the mixture was sealed andheated at 125° C. for 7 h. The mixture was cooled to rt, filtered, andthe filtrate subjected to purification by reverse-phase preparative HPLCeluting with a mixture of water (5% CH₃CN, 0.05% HOAc) and CH₃CN (0.05%HOAc) as the mobile phase and a Varian diphenyl column as the stationaryphase, to afford(1R,2R)-2-((6-((5-(methylsulfonyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(30 mg, 30%) as a white powder. ¹H NMR (300 MHz, DMSO-d₆) δ 8.69 (s,1H), 8.20 (s, 1H), 8.06 (d, J=7.5 Hz, 1H), 7.84 (m, 1H), 7.76 (m, 1H),7.69 (s, 1H), 7.30 (m, 1H), 7.21 (m, 1H), 5.56 (s, 2H), 4.82 (m, 1H),3.50 (m, 1H), 3.36 (m, 1H), 3.19 (s, 3H), 2.01 (m, 1H), 1.87 (m, 1H),1.56-1.67 (m, 2H), 1.11-1.31 (m, 4H); LCMS (ESI) m/z 457 (M+H)⁺.

Example 113 Preparation of(1R,2R)-2-((6-((6-(methylsulfonyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

(1R,2R)-2-((6-((6-(Methylsulfonyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolwas synthesized as a white powder (22 mg, 26%) using a procedureanalogous to that described in Example 112, substituting(1R,2R)-2-((6-((6-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(as prepared in Example 107, steps 1 through 6) for(1R,2R)-2-((6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolused in Example 112. ¹H NMR (300 MHz, DMSO-d₆) δ 8.69 (s, 1H), 8.21 (s,1H), 8.01 (d, J=7.3 Hz, 1H), 7.89 (d, J=8.5 Hz, 1H), 7.75 (m, 1H), 7.67(d, J=1.1 Hz, 1H), 7.32 (m, 1H), 7.20 (m, 1H), 5.60 (s, 2H), 4.76 (d,J=4.3 Hz, 1H), 3.51 (m, 1H), 3.35 (m, 1H), 3.21 (s, 3H), 2.02 (m, 1H),1.88 (m, 1H), 1.55-1.67 (m, 2H), 1.13-1.34 (m, 4H); LCMS (ESI) m/z 457(M+H)⁺.

Example 114 Preparation of(1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridine-3-yl)methyl)thiazolo[4,5-b]pyridine-2-yl)amino)cyclohexanol

Step 1: A mixture of ethyl 6-amino-5-bromonicotinate (1.0 g, 4 mmol) andO-ethylxanthic acid potassium salt (785 mg, 4.2 mmol) in DMF (15 mL) washeated at reflux for 6 h. The mixture was cooled to rt and waspartitioned between EtOAc (200 mL) and 1 M aq Na₂CO₃ (150 mL). A solidformed between the two layers and was collected by filtration. Thelayers were separated and the organic layer was concentrated underreduced pressure until a slurry began to form. The mixture was cooled to0° C. and the resulting solid was collected by filtration. The two solidbatches were combined to afford ethyl2-mercaptothiazolo[4,5-b]pyridine-6-carboxylate potassium salt (871 mg,89%), which did not require further purification. ¹H NMR (300 MHz,DMSO-d₆) δ 8.69 (d, J=2.1 Hz, 1H), 8.19 (d, J=2.1 Hz, 1H), 4.29 (q,J=7.0 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H); LCMS (ESI) m/z 241 (M+H)⁺.

Step 2: To a stirred mixture of ethyl2-mercaptothiazolo[4,5-b]pyridine-6-carboxylate potassium salt (1.7 g,6.6 mmol) from the previous step in DMF (10 mL) at 0° C. was addediodomethane (226 μL, 3.6 mmol). After the mixture was stirred at 0° C.for 2 h, it was allowed to warm slowly to rt. The mixture waspartitioned between EtOAc (100 mL) and 0.5 M aq Na₂CO₃ (50 mL). Theorganic layer was separated and washed with brine (50 mL), dried overMg₂SO₄, filtered, and concentrated under reduced pressure to affordethyl 2-(methylthio)thiazolo[4,5-b]pyridine-6-carboxylate (724 mg, 82%)as a yellow solid. The material was used in the next step withoutfurther purification. ¹H NMR (300 MHz, DMSO-d₆) δ 9.07 (s, 2H), 4.38 (q,J=7.0 Hz, 2H), 2.86 (s, 3H), 1.36 (t, J=7.1 Hz, 3H); LCMS (ESI) m/z 255(M+H)⁺.

Step 3: (2-(Methylthio)thiazolo[4,5-b]pyridin-6-yl)methanol wassynthesized as a white solid (404 mg, 67%) using a procedure analogousto that described in Step 3 of Example 36, substituting ethyl2-(methylthio)thiazolo[4,5-b]pyridine-6-carboxylate from the previousstep for ethyl 2-(methylthio)benzo[d]thiazole-6-carboxylate used inExample 36. ¹H NMR (300 MHz, DMSO-d₆) δ 8.51 (d, J=1.9 Hz, 1H), 8.42 (d,J=1.9 Hz, 1H), 5.44 (t, J=5.7 Hz, 1H), 4.63 (d, J=5.7 Hz, 2H), 2.82 (s,3H); LCMS (ESI) m/z 213 (M+H)⁺.

Step 4: To a stirred mixture of(2-(methylthio)thiazolo[4,5-b]pyridin-6-yl)methanol (404 mg, 2 mmol) inanhydrous CH₂Cl₂ (20 mL) at rt was added SOCl₂ (166 μL, 2.4 mmol). After3 h, the mixture was concentrated under reduced pressure to afford6-(chloromethyl)-2-(methylthio)thiazolo[4,5-b]pyridine (497 mg) as awhite solid. The material was used in the next step without furtherpurification. 1H NMR (300 MHz, DMSO-d₆) δ 8.65 (d, J=1.9 Hz, 1H), 8.60(d, J=1.9 Hz, 1H), 4.95 (s, 2H), 2.83 (s, 3H); LCMS (ESI) m/z 231(M+H)⁺.

Step 5: To a stirred mixture of DMF (5 mL) and sodium hydride (60% inmineral oil, 64 mg, 1.6 mmol) at 0° C. under argon, was added4-azabenzimidazole (204 mg, 1.1 mmol) in one portion. The mixture wasstirred for 5 min at 0° C. followed by dropwise addition of a solutionof 6-(chloromethyl)-2-(methylthio)thiazolo[4,5-b]pyridine (497 mg, 2.2mmol) in DMF (2 mL). The mixture was warmed slowly to rt then heated at70° C. for 18 h. The mixture was cooled to rt, then partitioned betweenEtOAc (150 mL) and 0.5 M aq Na₂CO₃ (50 mL). The organic layer wasseparated and washed with water (50 mL), then brine, dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by silica gel flash chromatography eluting with a gradient of100% CH₂Cl₂ to 5% MeOH in DCM to afford6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)thiazolo[4,5-b]pyridine(126 mg, 35%) as a yellow solid. The regiochemistry of the alkylationwas determined by 2-dimensional nuclear Overhauser effect (NOE)experiment. ¹H NMR (300 MHz, DMSO-d₆) δ 8.64-8.74 (m, 2H), 8.46 (d,J=2.1 Hz, 1H), 8.38 (dd, J=1.1, 4.7 Hz, 1H), 8.12 (dd, J=1.3, 8.1 Hz,1H), 7.31 (dd, J=4.7, 8.1 Hz, 1H), 5.67 (s, 2H), 2.80 (s, 3H); LCMS(ESI) m/z 314 (M+H)⁺.

Step 6:6-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)thiazolo[4,5-b]pyridinewas synthesized as a white foam (135 mg) using a procedure analogous tothat described in Step 6 of Example 36, substituting6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)thiazolo[4,5-b]pyridinefrom the previous step for6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole usedin Example 36. LCMS (ESI) m/z 330 (M+H)⁺.

Step 7:(1R,2R)-2-((6-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)thiazolo[4,5-b]pyridin-2-yl)amino)cyclohexanolwas synthesized as a white powder (80 mg, 53%) using a procedureanalogous to that described in Step 7 of Example 36, substituting6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)thiazolo[4,5-b]pyridinefrom the previous step for6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazoleused in Example 36. ¹H NMR (300 MHz, DMSO-d₆) δ 8.62 (s, 1H), 8.46 (d,J=7.5 Hz, 1H), 8.39 (dd, J=1.2, 4.8 Hz, 1H), 8.33 (d, J=2.1 Hz, 1H),8.09 (dd, J=1.3, 8.1 Hz, 1H), 8.05 (d, J=2.1 Hz, 1H), 7.30 (m, 1H), 5.50(s, 2H), 4.82 (d, J=5.3 Hz, 1H), 3.61 (m, 1H), 3.35 (m, 1H), 2.03 (m,1H), 1.88 (m, 1H), 1.55-1.70 (m, 2H), 1.15-1.33 (m, 4H); LCMS (ESI) m/z381 (M+H)⁺.

Example 115 Preparation of(1R,2R)-2-((6-((6-((R,S)-1-hydroxyethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

To a stirred solution of1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidadazo[4,5-b]pyridin-6-yl)ethanone(92 mg, 0.22 mmol) from Example 73, MeOH (5 mL) and DMF (3 mL) at rt wasadded sodium borohydride (17 mg, 0.44 mmol). The mixture was stirred atrt for 15 min. The reaction mixture was purified directly byreverse-phase HPLC using a mixture of water (5% CH₃CN, 0.05% HOAc) andCH₃CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenylcolumn as the stationary phase to afford(1R,2R)-2-((6-((6-((R,S)-1-hydroxyethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(38 mg, 41%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.55 (s, 1H),8.37 (d, J=1.5 Hz, 1H), 7.97-8.00 (m, 2H), 7.66 (m, 1H), 7.28 (d, J=6.0Hz, 1H), 7.20 (dd, J=6.0, 3.0 Hz, 1H), 5.46 (s, 2H), 5.30 (br m, 1H),4.90 (m, 1H), 4.76 (br m, 1H), 3.50 (m, 1H), 3.30 (m, 1H), 2.03 (m, 1H),1.87 (m, 1H), 1.55-1.65 (m, 2H), 1.40 (d, J=6.0 Hz, 3H), 1.10-1.30 (m,4H). LCMS (ESI) m/z 424 (M+H)⁺.

Example 116 Preparation of2-(dimethylamino)-1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-yl)ethanoneacetate salt

Step 1: A stirred mixture of(1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(693 mg, 1.51 mmol) from Example 29, tributyl (1-ethoxyvinyl)tin (1.10g, 3.03 mmol) and DMF (10 mL) was purged with argon. To the mixture wasadded tetrakis(triphenylphosphine)palladium (0) (262 mg, 0.23 mmol). Thereaction vessel was sealed and the mixture was heated at 110° C. for 2h. The mixture was allowed to cool to rt. The mixture was partitionedbetween water and DCM and the organic layer was separated. The aqueouslayer was extracted with additional DCM. The combined organic layerswere washed with water then brine, dried over magnesium sulfate,filtered, and concentrated under reduced pressure. The residue waspurified by silica gel flash chromatography eluting with 100% DCM to 15%MeOH in DCM to afford(1R,2R)-2-((6-((6-(1-ethoxyvinyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(320 mg, 47%) as a solid. LCMS (ESI) m/z 450 (M+H)⁺.

Step 2: To a stirred solution of(1R,2R)-2-((6-((6-(1-ethoxyvinyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(90 mg, 0.20 mmol) from the previous step in DMF (2 mL) at 0° C. wasadded N-bromosuccinimide (36 mg, 0.20 mmol), and the mixture was stirredfor 15 min. To the mixture was added dimethylamine (2M in THF, 0.90 mL,1.80 mmol) and stirring was continued at 0° C. for 5 min. The reactionmixture was purified directly by reverse-phase HPLC using a mixture ofwater (5% CH₃CN, 0.05% HOAc) and CH₃CN (0.05% HOAc) as the mobile phaseand Varian Pursuit XRs diphenyl column as the stationary phase to afford2-(dimethylamino)-1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)ethanoneacetate salt (5 mg, 5%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ9.01 (d, J=1.7 Hz, 1H), 8.75 (s, 1H), 8.67 (d, J=1.7 Hz, 1H), 8.03 (d,J=7.5 Hz, 1H), 7.68 (s, 1H), 7.20-7.32 (m, 2H), 5.52 (s, 2H), 4.80 (brs, 1H), 3.78 (s, 2H), 3.51 (br m, 1H), 3.30 (br m, 1H), 2.25 (s, 6H),2.04 (br m, 1H), 1.82-1.86 (m, 4H), 1.59-1.65 (br m, 2H), 1.10-1.60 (m,4H); LCMS (ESI) m/z 465 (M+H)⁺.

Example 117 Preparation of3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridine-7-carbonitrile

Step 1: A mixture of 2-fluoro-4-iodoaniline (2.4 g, 10 mmol) and sodiumO-ethyl carbonodithioate (3.2 g, 20 mmol) in DMF (8 mL) was stirred at95° C. for 5 h. The reaction mixture was cooled to rt then diluted withwater (25 mL) and 1 N aqueous HCl (20 mL). The mixture was stirred atroom temperature for 1 h. The resulting precipitate was collected byfiltration and washed with water. The solid was dried to afford6-iodobenzo[d]thiazole-2-thiol as a light yellow solid (3.3 g, 100%). ¹HNMR (300 MHz, CD₃OD) δ 7.89 (d, J=1.2 Hz, 1H), 7.67 (dd, J=1.8, 8.7 Hz,1H), 7.05 (d, J=8.4 Hz, 1H). LCMS (ESI) m/z 294 (M+H)⁺.

Step 2: To a stirred mixture of 6-iodobenzo[d]thiazole-2-thiol (0.5 g,1.7 mmmol) and potassium carbonate (0.23 g, 1.7 mmol) in THF (10 mL) wasadded methyl iodide (0.12 mL, 1.1 mmol). After stirring at rt overnight,the mixture was concentrated under reduced pressure to give a solid. Thesolid was partitioned between saturated aq sodium carbonate and DCM. Theorganic layer was dried over Na₂SO₄ and filtered, and concentrated underreduced pressure to give 6-iodo-2-(methylthio)benzo[d]thiazole as aoff-white solid (0.4 g, 76%). ¹H NMR (300 MHz, CDCl₃) δ 8.07 (d, J=1.2Hz, 1H), 7.69 (dd, J=1.8, 8.4 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 2.78 (s,3H). LCMS (ESI) m/z 308 (M+H)⁺.

Step 3: A mixture of 6-iodo-2-(methylthio)benzo[d]thiazole (5.0 g, 16.3mmol), allyl alcohol (2.2 mL, 32.6 mmol), Pd(OAc)₂ (0.36 g, 1.63 mmol),tris(o-tolyl) phosphine (1.0 g, 3.3 mmol) and NaHCO₃ (2.8 g, 32.6 mmol)in DMF (75 mL) was stirred at 100° C. under nitrogen atmosphere for 4 h.Then the mixture was cooled to rt and water (300 mL) was added. Themixture was extracted with EtOAc (200 mL×3). The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by silica gelchromatography eluting with 10:1 to 5:1 petroleum ether/EtOAc to afford3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal as a dark yellow oil (2.0g, 52%). ¹H NMR (300 MHz, CDCl₃) δ 9.83 (t, J=1.2 Hz, 1H), 7.78 (d,J=8.4 Hz, 1H), 7.58 (d, J=1.2 Hz, 1H), 7.23 (dd, J=1.8, 8.4 Hz, 1H),3.05 (t, J=7.5 Hz, 2H), 2.85 (t, J=7.5 Hz, 2H), 2.78 (s, 3H). LCMS (ESI)m/z 238 (M+H)⁺.

Step 4: L-proline (0.22 g, 1.9 mmol) was added to a solution of3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal (2.3 g, 9.7 mmol) in DCM(40 mL) at 0° C. followed by addition of N-chlorosuccinimide (1.4 g, 10mmol). The reaction mixture was slowly warmed to ambient temperature andstirred overnight. The reaction mixture was concentrated under reducedpressure and purified by silica gel chromatography, eluting with 10:1 to2:1 petroleum ether/EtOAc to afford2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal as a yellow oil(2.1 g, 79%). ¹H NMR (300 MHz, CDCl₃) δ 9.56 (dd, J=1.2, 2.1 Hz, 1H),7.81 (d, J=8.4 Hz, 1H), 7.63 (d, J=0.6 Hz, 1H), 7.28 (d, J=1.5 Hz, 1H),4.44-4.39 (m, 1H), 3.51-3.44 (m, 1H), 3.20-3.13 (m, 1H), 2.78 (s, 3H).LCMS (ESI) m/z 290 (M+18+H)⁺.

Step 5: A mixture of 4-bromopyridin-2-amine (4.9 g, 28.5 mmol), Zn(CN)₂(5.0 g, 42.5 mmol), Pd₂(dba)₃ (1.3 g, 1.4 mmol) and dppf (1.6 g, 2.8mmol) in DMF (150 mL) was stirred at 100° C. under nitrogen atmospherefor 1.5 h. The mixture was cooled to rt and water (500 mL) was added.The mixture was extracted with EtOAc (300 mL×3). The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography eluting with 10:1 to 2:1 petroleum ether/EtOAc toafford 2-aminoisonicotinonitrile as a light yellow solid (2.7 g, 80%).¹H NMR (300 MHz, CDCl₃) δ 8.19 (d, J=5.1 Hz, 1H), 6.82 (d, J=4.8 Hz,1H), 6.69 (d, J=0.9 Hz, 1H), 4.72 (br s, 2H). LCMS (ESI) m/z 120 (M+H)⁺.

Step 6: A mixture of2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal (0.35 g, 1.3mmol) and 2-aminoisonicotinonitrile (0.30 g, 2.6 mmol) in 1-butanol (15mL) was heated at reflux overnight. After cooling to rt, the formedsolid was collected and washed with water, then dried to afford3-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridine-7-carbonitrileas a white solid (0.27 g, 62%). ¹H NMR (300 MHz, CDCl₃) δ 8.45 (d, J=7.2Hz, 1H), 8.34 (s, 1H), 7.90 (s, 1H), 7.78 (d, J=8.7 Hz, 1H), 7.75 (s,1H), 7.37 (dd, J=1.2, 7.8 Hz, 1H), 7.20 (dd, J=1.8, 7.2 Hz, 1H), 4.49(s, 2H), 2.77 (s, 3H). LCMS (ESI) m/z 337 (M+H)⁺.

Step 7: To a solution of3-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridine-7-carbonitrile(0.27 g, 0.8 mmol) in DCM (15 mL) was added m-CPBA (0.17 g, 0.9 mmol) at0° C. The reaction mixture was stirred for 2 h at 0° C., then aq Na₂SO₃(15 mL) was added and the mixture was stirred for 0.5 h. The organiclayer was separated, dried over Na₂SO₄, filtered and concentrated underreduced pressure to afford3-((2-(methylsulfinyl)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridine-7-carbonitrileas a yellow solid (0.28 g, 99%). ¹H NMR (300 MHz, CDCl₃) δ 8.46 (d,J=7.2 Hz, 1H), 8.36 (s, 1H), 8.15 (d, J=1.2 Hz, 1H), 8.04 (d, J=8.7 Hz,1H), 7.78 (s, 1H), 7.55 (dd, J=1.5, 8.4 Hz, 1H), 7.21 (dd, J=1.8, 7.2Hz, 1H), 4.57 (s, 2H), 3.06 (s, 3H). LCMS (ESI) m/z 353 (M+H)⁺.

Step 8: A mixture of 3-((2-(methylsulfinyl)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridine-7-carbonitrile (0.20 g, 0.56 mmol),(1R,2R)-2-amino cyclohexanol (97 mg, 0.84 mmol) and DIEA (0.18 g, 1.4mmol) in DMA (10 mL) was stirred for 2 d at 140° C. The mixture wascooled to rt and water (50 mL) was added. The mixture was extracted withEtOAc (30 mL×3). The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography eluting with 50:1 to10:1 DCM/MeOH to afford a solid, which was recrystallized in 10:1DCM/MeOH (10 mL) to afford3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridine-7-carbonitrileas a white solid (75 mg, 33%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.40 (d,J=6.9 Hz, 1H), 8.32 (s, 1H), 7.88 (d, J=6.9 Hz, 1H), 7.72 (s, 1H), 7.53(s, 1H), 7.27 (d, J=8.1 Hz, 1H), 7.19 (d, J=6.9 Hz, 1H), 7.09 (d, J=7.5Hz, 1H), 4.73 (d, J=4.2 Hz, 1H), 4.36 (s, 2H), 3.54-3.50 (m, 1H),3.37-3.34 (m, 1H), 2.05-2.01 (m, 1H), 1.90-1.86 (m, 1H), 1.65-1.59 (m,2H), 1.30-1.16 (m, 4H). LCMS (ESI) m/z 404 (M+H)⁺.

Example 118 Preparation of(1R,2R)-2-((6-((9H-purin-9-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol

Step 1: A solution of pyrimidine-4,5-diamine (718 mg, 6.53 mmol) andHCOOH (0.36 mL) in triethoxymethane (19 mL) was stirred at 90° C. for3.5 h. The reaction mixture was concentrated under reduced pressure. Theresidue was purified by silica gel chromatography eluting with 40:1DCM/MeOH to give 9H-purine as a brown solid (784 mg, 100%). ¹H NMR (300MHz, DMSO-d₆) δ 13.40 (br s, 1H), 9.12 (s, 1H), 8.92 (s, 1H), 8.60 (s,1H). LCMS (ESI) m/z 121 (M+H)⁺.

Step 2: To a stirred solution of 9H-purine (784 mg, 6.53 mmol) in DMF(16 mL) was added NaH (60% dispersion in mineral oil, 373 mg, 9.33 mmol)portionwise at 0° C. After stirring for 30 min,6-(chloromethyl)-2-(methylthio)benzo[d]oxazole (1.3 g, 6.22 mmol) wasadded to the mixture. The reaction mixture was allowed to warm to rt andstir for 3 h. The reaction mixture was poured into water (150 mL) andextracted with ethyl acetate (150 mL×4). The combined organic layerswere washed with water and brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography eluting with 40:1 DCM/MeOH to give6-((9H-purin-9-yl)methyl)-2-(methylthio)benzo[d]oxazole as a lightyellow solid (569 mg, 32.7%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.14 (s, 1H),8.92 (s, 1H), 8.77 (s, 1H), 7.69 (s, 1H), 7.56 (d, J=7.8 Hz, 1H), 7.35(d, J=9.0 Hz, 1H), 5.59 (s, 2H), 2.70 (s, 3H). LCMS (ESI) m/z 298(M+H)⁺.

Step 3: A mixture of6-((9H-purin-9-yl)methyl)-2-(methylthio)benzo[d]oxazole (400 mg, 1.35mmol) and m-CPBA (289 mg, 1.69 mmol) in DCM (25 mL) was stirred at 0° C.for 6 h. The reaction mixture was washed with aq Na₂S₂O₃ and brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography eluting with 1:5petroleum ether/ethyl acetate to give6-((9H-purin-9-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole as a lightyellow solid (143 mg, 33.89%). ¹H NMR (300 MHz, CDCl₃) δ 9.18 (s, 1H),9.03 (s, 1H), 8.13 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.66 (s, 1H), 7.44(d, J=9.9 Hz, 1H), 5.62 (s, 2H), 3.18 (s, 3H). LCMS (ESI) m/z 314(M+H)⁺.

Step 4: A mixture of 6-((9H-purin-9-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole (106 mg, 0.34 mmol),(1R,2R)-2-aminocyclohexanol (77 mg, 0.51 mg) and DIEA (132 mg, 1.02mmol) in DMA (3 mL) was stirred at 135° C. for 2 h. The reaction mixturewas cooled to rt, poured into water (30 mL) and extracted with ethylacetate (20 mL×2). The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography eluting with 1:6petroleum ether/ethyl acetate to give crude product, which was washedwith 10:1 petroleum ether/ethyl acetate to afford(1R,2R)-2-((6-((9H-purin-9-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanolas a light yellow solid (68 mg, 48.57%). ¹H NMR (300 MHz, DMSO-d₆) δ9.16 (s, 1H), 8.96 (s, 1H), 8.73 (s, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.42(s, 1H), 7.16 (d, J=1.2 Hz, 1H), 7.14 (d, J=8.1 Hz, 1H) 5.51 (s, 2H),4.66 (d, J=4.2 Hz, 1H), 3.34 (br s, 2H), 1.90 (br s, 2H), 1.60 (br s,2H), 1.22 (br s, 4H). LCMS (ESI) m/z 365 (M+H)⁺.

Example 119 Preparation of(1R,2R)-2-((6-((5,6-dimethyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: To a stirred mixture of anhydrous DMF (15 mL) and sodium hydride(60% dispersion in mineral oil, 105 mg, 2.63 mmol) at 0° C. undernitrogen, was added portionwise 5,6-dimethyl-1H-benzo[d]imidazole (215mg, 1.4 mmol). The reaction mixture was stirred for 5 min. A solution of6-(chloromethyl)-2-(methylthio)benzo[d]thiazole (320 mg, 1.4 mmol) fromStep 4 of Example 36 in anhydrous DMF (2 mL) was added dropwise. Thereaction mixture was allowed to warm to rt and stir for 1 h. Thereaction solution was poured into ice-water and extracted with EtOAc (50mL×3). The combined organic layers were further washed with water (20mL), then brine (20 mL). The organic layer was separated, dried overNa₂SO₄, filtered, and concentrated under reduced pressure to afford6-((5,6-dimethyl-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole(450 mg, 96%) as a yellow solid which was not purified further. ¹H NMR(300 MHz, CDCl₃) δ 7.86 (s, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.59 (s, 1H),7.46 (s, 1H), 7.24-7.26 (m, 1H), 7.03 (s, 1H), 5.40 (s, 2H), 2.77 (s,3H), 2.37 (s, 3H), 2.32 (s, 3H); LCMS (ESI) m/z 340 (M+H)⁺.

Step 2: To a stirred solution of6-((5,6-dimethyl-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole(450 mg, 1.32 mmol) from the previous step in DCM (20 mL) at 0° C. wasadded a solution of meta-chloroperbenzoic acid (270 mg, 1.32 mmol) inDCM (3 mL). After stirring for 2 h at 0° C., the reaction solution wasdiluted with EtOAc (100 mL) and washed sequentially with saturated aqNa₂S₂O₃, saturated aq NaHCO₃, and brine. The organic layer was driedover Na₂SO₄, filtered, and concentrated under reduced pressure to afford6-((5,6-dimethyl-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole(460 mg, 98%) as a colorless solid which was not purified further. ¹HNMR (300 MHz, CDCl₃) δ 8.01 (d, J=8.4 Hz, 1H), 7.90 (s, 1H), 7.72 (s,1H), 7.60 (s, 1H), 7.37 (m, 1H), 7.02 (s, 1H), 5.48 (s, 2H), 3.06 (s,3H), 2.37 (s, 3H), 2.32 (s, 3H); LCMS (ESI) m/z 356 (M+H)⁺.

Step 3: A stirred mixture of6-((5,6-dimethyl-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole(150 mg, 0.42 mmol) from the previous step, (1R,2R)-2-aminocyclohexanol(140 mg, 1.2 mmol), DIEA (540 mg, 4.2 mmol) and NMP (2 mL) was heated at130° C. for 12 h. The reaction mixture was cooled to rt, diluted withEtOAc (30 mL) and washed with water (10 mL×2). The organic layer wasseparated, dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by silica gel flash chromatographyeluting with 3% MeOH in DCM to afford(1R,2R)-2-((6-((5,6-dimethyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(80 mg, 47%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.22 (s, 1H),7.92 (d, J=6.0 Hz, 1H), 7.58 (m, 1H), 7.41 (s, 1H), 7.26-7.31 (m, 2H),7.14 (m, 1H), 5.40 (s, 2H), 4.71 (d, J=3.0 Hz, 1H), 3.50 (m, 1H), 3.35(m, 1H), 2.30 (s, 6H), 2.02 (m, 1H), 1.88 (m, 1H), 1.86-1.90 (m, 2H),1.12-1.27 (m, 4H); LCMS (ESI) m/z 407 (M+H)⁺.

Example 120 Preparation of1-(1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-6-yl)ethanone

1-(1-((2-(((1R,2R)-2-Hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-6-yl)ethanonewas synthesized as a white powder (8 mg, 6%) using a procedure analogousto that described in Example 110, substituting(1R,2R)-2-((6-((6-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolfrom Step 6 of Example 107 for(1R,2R)-2-((6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolused in Example 110. ¹H NMR (300 MHz, DMSO-d₆) δ 8.60 (s, 1H), 8.24 (s,1H), 7.99 (d, J=7.5 Hz, 1H), 7.82 (m, 1H), 7.74 (m, 1H), 7.68 (s, 1H),7.31 (m, 1H), 7.21 (m, 1H), 5.58 (s, 2H), 4.75 (d, J=5.1 Hz, 1H), 3.51(m, 1H), 3.35 (m, 1H), 2.61 (s, 3H), 2.02 (m, 1H), 1.87 (m, 1H),1.55-1.67 (m, 2H), 1.10-1.34 (m, 4H); LCMS (ESI) m/z 421 (M+H)⁺.

Example 121 Preparation of(1R,2R)-2-((6-((5-ethynyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: A stirred mixture of(1R,2R)-2-((6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(109 mg, 0.24 mmol) from Step 6 of Example 108,(trimethylsilyl)acetylene (68 μL, 0.48 mmol), and DIEA (62 μL, 0.36mmol) in CH₃CN (2 mL), was purged with a stream of argon for 5 min. Tothe mixture was added tetrakis(triphenylphosphine)palladium (0) (57 mg,0.05 mmol) and argon was bubbled into the mixture for an additional 5min. The reaction vessel was sealed and the mixture was heated at 80° C.for 5 h. The mixture was cooled to rt and was partitioned between EtOAc(100 mL) and 1 M aq NaHCO₃ (50 mL). The organic layer was washed withbrine (50 mL), dried over Mg₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by silica gel flashchromatography eluting with 5% MeOH in DCM to afford(1R,2R)-2-((6-((5-((trimethylsilyl)ethynyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(61 mg, 54%) as an amber oil. LCMS (ESI) m/z 476 (M+H)⁺.

Step 2: A mixture of(1R,2R)-2-((6-((5-((trimethylsilyl)ethynyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(61 mg, 0.13 mmole) and Na₂CO₃ (177 mg, 1.3 mmole) in MeOH (2 mL) wasstirred at rt for 2 h. The mixture was filtered and the filtrate wasconcentrated under reduced pressure. The residue was purified byreverse-phase preparative HPLC using a mixture of water (5% CH₃CN, 0.05%HCOOH) and CH₃CN (0.05% HCOOH) as the mobile phase and a Varian PursuitXRs C18 column as the stationary phase to afford(1R,2R)-2-((6-((5-ethynyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(8 mg, 17%) as a white powder. ¹H NMR (300 MHz, DMSO-d₆) δ 8.49 (s, 1H),8.01 (d, J=7.3 Hz, 1H), 7.76 (s, 1H), 7.65 (s, 1H), 7.57 (d, J=8.3 Hz,1H), 7.27-7.33 (m, 2H), 7.19 (m, 1H), 5.48 (s, 2H), 4.78 (d, J=4.9 Hz,1H), 4.03 (s, 1H), 3.51 (m, 1H), 3.35 (m, 1H), 2.03 (m, 1H), 1.87 (m,1H), 1.56-1.69 (m, 2H), 1.11-1.31 (m, 4H); LCMS (ESI) m/z 405 (M+H)⁺.

Example 122 Preparation of(1R,2R)-2-((6-((6-ethynyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1:(1R,2R)-2-((6-((6-((Trimethylsilyl)ethynyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolwas synthesized as an oil (46 mg, 41%) using a procedure analogous tothat described in Step 1 of Example 121, substituting(1R,2R)-2-((6-((6-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolfrom Step 6 of Example 107 for(1R,2R)-2-((6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolused in Example 121. LCMS (ESI) m/z 476 (M+H)⁺.

Step 2:(1R,2R)-2-((6-((6-Ethynyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolwas synthesized as a powder (7 mg, 18%) using a procedure analogous tothat described in Step 2 of Example 121, substituting(1R,2R)-2-((6-((6-((trimethylsilyl)ethynyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolfrom the previous step for(1R,2R)-2-((6-((5-((trimethylsilyl)ethynyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolused in Example 121. ¹H NMR (300 MHz, DMSO-d₆) δ 8.50 (s, 1H), 8.03 (d,J=7.2 Hz, 1H), 7.74 (s, 1H), 7.60-7.68 (m, 2H), 7.16-7.34 (m, 3H), 5.48(s, 2H), 4.80 (d, J=4.0 Hz, 1H), 4.10 (s, 1H), 3.51 (m, 1H), 3.35 (m,1H), 2.02 (m, 1H), 1.87 (m, 1H), 1.56-1.67 (m, 2H), 1.11-1.34 (m, 4H);LCMS (ESI) m/z 405 (M+H)⁺.

Example 123 Preparation of(1R,2R)-2-((6-((6-bromo-5-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: To a stirred solution of 6-methoxy-3-nitropyridin-2-amine (1.56g, 9.2 mmol) in 15 mL of DMF at rt was added N-bromosuccimide (1.81 g,10.1 mmol) in portions. The resulting mixture was stirred at rt for 1 h.TLC showed the reaction was complete. The reaction mixture was quenchedwith water and the reddish brown solid was collected by filtration,washed with water, and dried in a vacuum oven to give5-bromo-6-methoxy-3-nitropyridin-2-amine (2.1 g, 92%). LCMS (ESI) m/z248, 250 (M+H)⁺.

Step 2: A mixture of acetic anhydride (15.9 mL, 168.7 mmol) and formicacid (6.4 mL, 168.7 mmol) was heated at 60° C. for 3 h. After cooling tort, 5-bromo-6-methoxy-3-nitropyridin-2-amine (2.1 g, 8.4 mmol) from Step1 of this Example was added in portions. The resulting mixture washeated at 60° C. for 1 h, then at 70° C. for 1 h. LCMS analysis showedthat the reaction was complete. The volume was condensed under reducedpressure, and the precipitated solid was collected by filtration to giveN-(5-bromo-6-methoxy-3-nitropyridin-2-yl)formamide as a light yellowsolid (2.2 g, 94%). LCMS (ESI) m/z 276, 278 (M+H)⁺.

Step 3: CrudeN-(5-bromo-6-methoxy-3-nitropyridin-2-yl)-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)formamide(950 mg) was obtained as a light yellow solid using a procedureanalogous to that described in Step 4 of Example 3, substitutingN-(5-bromo-6-methoxy-3-nitropyridin-2-yl)formamide from Step 2 of thisExample for 3H-imidazo[4,5-b]pyridine used in Example 3. LCMS (ESI) m/z469, 471 (M+H)⁺.

Step 4: To a stirred solution of crudeN-(5-bromo-6-methoxy-3-nitropyridin-2-yl)-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)formamide(950 mg, 2.0 mmol) in EtOH (8 mL) were added AcOH (2 mL) and iron (169mg, 3.0 mmol). The resulting mixture was heated at reflux for 1 h.Another portion of iron (169 mg, 3.0 mmol) was added and heating wascontinued for 1 h at 105° C. LCMS analysis showed that the reaction wascomplete. The mixture was allowed to cool to rt, and then water wasadded. Crude6-((6-bromo-5-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazolewas collected by filtration as a brownish green solid (1.01 g). LCMS(ESI) m/z 421, 423 (M+H)⁺.

Step 5:(1R,2R)-2-((6-((6-Bromo-5-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(115 mg, 23%) was obtained as a light yellow solid using proceduresanalogous to those described in Step 5 of Example 3 followed by Step 5of Example 2, substituting6-((6-bromo-5-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazolefrom Step 4 of this Example for6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazoleused in Example 3, and substituting the product of that reaction for2-bromo-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazoleused in Example 2. ¹H NMR (300 MHz, DMSO-d₆) δ 8.41 (s, 1H), 8.35 (s,1H), 7.97 (d, J=7.5 Hz, 1H), 7.73 (s, 1H), 7.29 (s, 2H), 5.39 (s, 2H),4.75 (br s, 1H), 4.01 (s, 3H), 3.50 (br s, 2H), 2.04 (br s, 1H),1.80-1.88 (m, 1H), 1.60 (br s, 2H), 1.22 (d, J=5.8 Hz, 4H). LCMS (ESI)m/z 488, 490 (M+H)⁺.

Example 124 Preparation of3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]oxazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile

Step 1: A solution of 5-bromo-pyridine-2,3-diamine (3.0 g, 15.96 mmol)and HCOOH (1.1 mL) in triethoxymethane (48 mL) was stirred at 90° C. for3 h. The reaction mixture was concentrated under reduced pressure. Theresidue was purified by silica gel chromatography eluting with 40:1DCM/MeOH to give 6-bromo-3H-imidazo[4,5-b]pyridine as a light brownsolid (2.74 g, 86.7%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.49 (s, 1H), 8.44(s, 1H), 8.30 (br s, 1H). LCMS (ESI) m/z 198 (M+H)⁺.

Step 2: To a stirred solution of 6-bromo-3H-imidazo[4,5-b]pyridine (200mg, 1.01 mmol) in DMF (16 mL) was added NaH (60% dispersion in mineraloil, 581 mg, 1.44 mmol) portionwise at 0° C. After the mixture wasstirred for 30 min, 6-(chloromethyl)-2-(methylthio)benzo[d]oxazole (203mg, 0.96 mmol) was added. The reaction mixture was allowed to warm to rtand stir for 2 h. The reaction mixture was poured into water (40 mL) andextracted with ethyl acetate (60 mL×4). The combined organic layers werewashed with water and brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified bypreparative TLC eluting with 15:1 DCM/MeOH to give6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]oxazole(156 mg, 43.2%) as a light yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ8.47 (s, 1H), 8.22 (s, 1H), 8.04 (s, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.40(s, 1H), 7.26 (d, J=6.6 Hz, 1H), 5.53 (s, 2H), 2.74 (s, 3H). LCMS (ESI)m/z 374 (M+H)⁺.

Step 3: A mixture of6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]oxazole(522 mg, 1.39 mmol) and m-CPBA (282 mg, 1.39 mmol) in DCM (20 mL) wasstirred at 0° C. for 5 h. The reaction mixture was washed with aqNa₂S₂O₃ and brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by silica gel chromatographyeluting with 1:1 to 1:5 petroleum ether/ethyl acetate to give6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]oxaz-oleas a light yellow solid (400 mg, 73.7%). ¹H NMR (300 MHz, DMSO-d₆) δ8.69 (s, 1H), 8.48 (s, 1H), 8.40 (s, 1H), 7.68 (s, 1H), 7.58 (d, J=8.1Hz, 1H), 7.34 (d, J=9.3 Hz, 1H), 5.60 (s, 2H), 2.73 (s, 3H). LCMS (ESI)m/z 390 (M+H)⁺.

Step 4: A mixture of6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole (330 mg, 0.84 mmol),(1R,2R)-2-aminocyclohexanol (192 mg, 1.27 mg) and DIEA (327 mg, 2.54mmol) in DMA (15 mL) was stirred at 135° C. for 1 h. The reactionmixture was cooled to rt, poured into water (100 mL) and extracted withethyl acetate (50 mL×3). The combined organic layers were washed withwater and brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by silica gel chromatographyeluting with 1:6 petroleum ether/ethyl acetate to give(1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanolas a light yellow solid (373 mg, 100%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.65(s, 1H), 8.48 (s, 1H), 8.38 (s, 1H), 7.79 (d, J=7.5 Hz, 1H), 7.38 (s,1H), 7.13 (s, 1H), 5.48 (s, 2H), 4.68 (s, 3H), 3.37 (br s, 2H), 1.92 (brs, 2H), 1.62 (br s, 2H), 1.23 (br s, 4H). LCMS (ESI) m/z 441 (M+H)⁺.

Step 5: A mixture of(1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol(276 mg, 0.62 mmol), Zn(CN)₂ (110 mg, 0.94 mmol), Pd₂(dba)₃ (57 mg,0.062 mmol) and dppf (68.8 mg, 0.124 mmol) in DMF (6 mL) was stirred at100° C. for 2 h. The reaction mixture was cooled to rt, poured intowater (100 mL) and extracted with ethyl acetate (100 mL×2). The combinedorganic layers were washed with water and brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by silica gel chromatography eluting with 15:1 DCM/MeOH to give3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]oxazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrileas a light yellow solid (62 mg, 25.8%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.85(s, 1H), 8.83 (d, J=1.5 Hz, 1H), 8.70 (s, 1H), 7.81 (d, J=7.8 Hz, 1H),7.41 (s, 1H), 7.14 (m, 2H), 5.54 (s, 2H), 4.68 (d, J=4.8 Hz, 1H), 3.34(br s, 2H), 1.91 (br s, 2H), 1.62 (br s, 2H), 1.22 (br, 4H). LCMS (ESI)m/z 389 (M+H)⁺.

Example 125 Preparation of(1R,2R)-2-((6-(imidazo[1,2-a]pyrazin-3-ylmethyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: A stirred mixture of2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal from Step 4 ofExample 117 (300 mg, 1.1 mmol) and pyrazin-2-amine (210 mg, 2.2 mmol) in1-butanol (10 mL) was heated at reflux overnight. The mixture was cooledto rt and water (20 mL) was added. The mixture was extracted with EtOAc(10 mL×3). The combined organic layers were washed with brine, driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography eluting with 50:1 to20:1 DCM/MeOH to afford6-(imidazo[1,2-a]pyrazin-3-ylmethyl)-2-(methylthio)benzo[d]thiazole as ayellow solid (120 mg, 35%). ¹H NMR (300 MHz, CDCl₃) δ 9.10 (d, J=1.2 Hz,1H), 7.83-7.80 (m, 2H), 7.72-7.68 (m, 2H), 7.50 (d, J=9.0 Hz, 1H), 7.23(d, J=1.8 Hz, 1H), 4.38 (s, 2H), 2.78 (s, 3H). LCMS (ESI) m/z 313(M+H)⁺.

Step 2: To a solution of6-(imidazo[1,2-a]pyrazin-3-ylmethyl)-2-(methylthio)benzo[d]thiazole (230mg, 0.74 mmol) from the previous step in DCM (14 mL) was added m-CPBA(160 mg, 0.93 mmol) at 0° C. The reaction mixture was stirred for 2 h at0° C., then aq Na₂S₂O₃ (15 mL) was added and the mixture was stirred for0.5 h. The organic layer was separated, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography, eluting with 50:1 to 20:1 DCM/MeOH, to afford6-(imidazo[1,2-a]pyrazin-3-ylmethyl)-2-(methylsulfinyl)benzo[d]thiazoleas a yellow solid (200 mg, 83%). ¹H NMR (300 MHz, CDCl₃) δ 9.13 (d,J=1.5 Hz, 1H), 8.02 (d, J=8.7 Hz, 1H), 7.85-7.79 (m, 2H), 7.74-7.70 (m,2H), 7.40 (dd, J=1.5, 8.4 Hz, 1H), 4.46 (s, 2H), 3.07 (s, 3H). LCMS(ESI) m/z 329 (M+H)⁺.

Step 3: A mixture of6-(imidazo[1,2-a]pyrazin-3-ylmethyl)-2-(methylsulfinyl)benzo[d]thiazole(350 mg, 1.07 mmol), (1R,2R)-2-aminocyclohexanol (324 mg, 2.14 mmol) andDIEA (414 mg, 3.21 mmol) in NMP (14 mL) was stirred for 2 d at 140° C.The mixture was cooled to rt and water (50 mL) was added. The mixturewas extracted with EtOAc (30 mL×3). The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by silica gel chromatographyeluting with 50:1 to 10:1 DCM/MeOH to afford 100 mg of solid. The solidwas recrystallized with 10:1 DCM/MeOH to afford(1R,2R)-2-((6-(imidazo[1,2-a]pyrazin-3-ylmethyl)benzo[d]thiazol-2-yl)amino)cyclohexanolas a white solid (70 mg, 17%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.03 (d,J=1.2 Hz, 1H), 8.33 (dd, J=1.8, 4.5 Hz, 1H), 7.88-7.85 (m, 2H), 7.68 (s,1H), 7.54 (s, 1H), 7.27 (d, J=7.8 Hz, 1H), 7.11 (dd, J=1.5, 7.8 Hz, 1H),4.71 (d, J=4.8 Hz, 1H), 4.35 (s, 2H), 3.52-3.49 (m, 1H), 3.39-3.36 (m,1H), 2.05-2.01 (m, 1H), 1.90-1.86 (m, 1H), 1.65-1.59 (m, 2H), 1.30-1.16(m, 4H). LCMS (ESI) m/z 380 (M+H)⁺.

Example 126 Preparation of3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-5-methoxy-3H-imidazo[4,5-b]pyridine-6-carbonitrile

3-((2-(((1R,2R)-2-Hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-5-methoxy-3H-imidazo[4,5-b]pyridine-6-carbonitrile(55 mg, 69%) was obtained as a light yellow solid using a proceduresanalogous to that described in Example 43, substituting(1R,2R)-2-((6-((6-bromo-5-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolfrom Example 123 for(1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolused in Example 43. ¹H NMR (300 MHz, DMSO-d₆) δ 8.60 (d, J=6.6 Hz, 2H),7.99 (d, J=7.3 Hz, 1H), 7.74 (s, 1H), 7.30 (s, 2H), 5.42 (s, 2H), 4.76(br s, 1H), 4.07 (s, 3H), 3.51-3.70 (m, 2H), 1.97-2.14 (m, 1H), 1.86 (brs, 1H), 1.62 (d, J=4.5 Hz, 2H), 1.22 (d, J=5.5 Hz, 4H). LCMS (ESI) m/z435 (M+H)⁺.

Example 127 Preparation of(1R,2R)-2-((6-((5-methyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: To a stirred mixture of 4-methyl-2-nitroaniline (1 g, 6.5 mmol)in TFA (15 mL) at 0 to 5° C. was added portionwise sodiumtriacetoxyborohydride (2.78 g, 13.2 mmol) and the mixture was stirredfor 10 min. To the reaction mixture was added portionwise2-(methylthio)benzo[d]thiazole-6-carbaldehyde (1.44 g, 6.9 mmol) fromStep 1 of Example 100. After stirring at rt for 4 h, the mixture waspoured into ice-water and extracted with EtOAc (100 mL×3). The combinedorganic layers were washed with saturated aq NaHCO₃ (100 mL×2) and brine(100 mL). The organic layer was separated, dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified bysilica gel flash chromatography eluting with 3% EtOAc in petroleum etherto afford4-methyl-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroaniline(0.93 g, 41%) as a yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.37 (br s,1H), 8.01 (s, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.71 (s, 1H), 7.38 (dd,J=8.4, 2.4 Hz, 1H), 7.19 (dd, J=8.7, 2.1 Hz, 1H), 8.71 (d, J=8.7 Hz,1H), 4.83 (d, J=6.0 Hz, 2H), 2.83 (s, 3H), 2.25 (s, 3H); LCMS (ESI) m/z346 (M+H)⁺.

Step 2: A mixture of4-methyl-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl 1)-2-nitroaniline(0.93 g, 2.7 mmol) from the previous step, MeOH (50 mL) and palladium onactivated charcoal (100 mg) was stirred under hydrogen at 1 atm pressureat rt for 12 h. The mixture was filtered and the filtrate wasconcentrated under reduced pressure to afford4-methyl-N¹-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine(0.70 g, 85%) as a brown solid which was not purified further. LCMS(ESI) m/z 316 (M+H)⁺.

Step 3: A stirred mixture of crude4-methyl-N¹-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine(0.7 g, 2.3 mmol), formic acid (0.5 mL) and triethyl orthoformate (5 mL)was heated at 100° C. for 1 h. The reaction mixture was cooled to rt andconcentrated under reduced pressure. The residue was purified by silicagel flash chromatography eluting with 3% MeOH in DCM to afford6-((5-methyl-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole(0.61 g, 85%) as a yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 7.94 (s, 1H),7.82 (d, J=8.4 Hz, 1H), 7.62 (s, 1H), 7.49 (s, 1H), 7.26 (m, 1H), 7.14(d, J=8.1 Hz, 1H), 7.07 (d, J=8.1 Hz, 1H), 5.43 (s, 2H), 2.77 (s, 3H),2.47 (s, 3H); LCMS (ESI) m/z 326 (M+H)⁺.

Step 4: To a stirred solution of6-((5-methyl-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole(0.61 g, 1.8 mmol) from the previous step in DCM (20 mL) at 0° C. wasadded a solution of meta-chloroperbenzoic acid (0.40 g, 1.57 mmol) inDCM (3 mL). After stirring for 2 h at 0° C., the solution was dilutedwith EtOAc (100 mL) and washed sequentially with saturated aq Na₂S₂O₃,saturated aq NaHCO₃, and brine. The organic layer was separated, driedover Na₂SO₄, filtered, and concentrated under reduced pressure to afford6-((5-methyl-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (0.57 g, 89%) as a yellow solid which was notpurified further.

Step 5: A stirred mixture of6-((5-methyl-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole(0.26 g, 0.76 mmol) from the previous step, (1R,2R)-2-aminocyclohexanol(0.26 g, 2.2 mmol), DIEA (0.98 g, 7.6 mmol) and NMP (2 mL) was heated at130° C. for 12 h. The reaction mixture was cooled to rt, diluted withEtOAc (30 mL), and washed with water (10 mL×2). The organic layer wasdried over Na₂SO₄, filtered, and concentrated under reduced pressure.The residue was purified by silica gel flash chromatography eluting with3% MeOH in DCM to afford(1R,2R)-2-((6-((5-methyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(79 mg, 89%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.30 (s, 1H),7.91 (d, J=7.5 Hz, 1H), 7.61 (d, J=2.0 Hz, 1H), 7.39-7.42 (m, 2H), 7.28(d, J=8.1 Hz, 1H), 7.16 (dd, J=8.4, 1.8 Hz, 1H), 7.02 (d, J=7.2 Hz, 1H),5.42 (s, 2H), 4.69 (d, J=5.1 Hz, 1H), 3.39 (m, 1H), 3.33 (m, 1H), 2.38(s, 3H), 2.03 (m, 1H), 1.86 (m, 1H), 1.59-1.63 (m, 2H), 1.21-1.23 (m,4H); LCMS (ESI) m/z 393 (M+H)⁺.

Example 128 Preparation of(1R,2R)-2-((6-((5,6-difluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: A mixture of 4,5-difluoro-2-nitroaniline (1.73 g, 10 mmol),palladium on activated charcoal (200 mg), and MeOH (50 mL) was stirredunder hydrogen (1 atm) at rt for 12 h. The mixture was filtered toremove the catalyst and the filtrate was concentrated under reducedpressure to afford 4,5-difluorobenzene-1,2-diamine (1.42 g, 97%) as abrown solid, which was not purified further. ¹H NMR (300 MHz, CDCl₃) δ6.50 (m, 2H), 2.75-3.48 (br s, 4H).

Step 2: A stirred mixture of 4,5-difluorobenzene-1,2-diamine (1.40 g,9.7 mmol) from the previous step, formic acid (2.0 mL), and triethylorthoformate (20 mL) was heated at 100° C. for 1 h. The reaction mixturewas cooled to rt and concentrated under reduced pressure. The residuewas purified by silica gel flash chromatography eluting with 5% MeOH inDCM to afford 5,6-difluoro-1H-benzo[d]imidazole as (1.12 g, 75%) as awhite solid. ¹H NMR (300 MHz, CDCl₃) δ 8.07 (s, 1H), 7.44 (m, 2H); LCMS(ESI) m/z 155 (M+H)⁺.

Step 3: To a stirred mixture of sodium hydride (60% dispersion inmineral oil, 0.144 g, 3.0 mmol) in anhydrous DMF (10 mL) at 0° C. undera nitrogen atmosphere was added portionwise6-difluoro-1H-benzo[d]imidazole (0.475 g, 2.0 mmol) from the previousstep. The mixture was stirred at 0° C. for 5 min. To the mixture wasadded dropwise a solution of6-(chloromethyl)-2-(methylthio)benzo[d]thiazole (0.32 g, 2.0 mmol) fromStep 4 of Example 36 in anhydrous DMF (2 mL). The reaction mixture wasallowed to warm to rt and stir for 1 h. The mixture was poured intoice-water and extracted with EtOAc (100 mL×2). The combined organiclayers were further washed with water (20 mL) then brine (20 mL). Theorganic layer was separated and dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to afford6-((5,6-difluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole(0.55 g, 76%) as a yellow solid, which was not purified further. ¹H NMR(300 MHz, CDCl₃) δ 7.97 (s, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.59 (m, 1H),7.50 (s, 1H), 7.24 (m, 1H), 7.02 (m, 1H), 5.40 (s, 2H), 2.78 (s, 3H);LCMS (ESI) m/z 348 (M+H)⁺.

Step 4: To a stirred solution of6-((5,6-difluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole(0.55 g, 1.58 mmol) from the previous step in DCM (20 mL) at 0° C. wasadded a solution of meta-chloroperbenzoic acid (0.32 g, 1.58 mmol) inDCM (3 mL). After stirring for 2 h at 0° C., the mixture was dilutedwith EtOAc (100 mL) and washed sequentially with saturated aq Na₂S₂O₃,saturated aq NaHCO₃, and brine. The organic layer was separated, driedover Na₂SO₄, filtered, and concentrated under reduced pressure to afford6-((5,6-difluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole(0.50 g, 88%) as a white solid, which was not purified further. ¹H NMR(300 MHz, CDCl₃) δ 8.02-8.06 (m, 2H), 7.77 (s, 1H), 7.61 (m, 1H), 7.37(dd, J=8.4, 1.5 Hz, 1H), 7.01 (m, 1H), 5.48 (s, 2H), 3.07 (s, 3H); LCMS(ESI) m/z 364 (M+H)⁺.

Step 5: A stirred mixture of6-((5,6-difluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole(0.20 g, 0.55 mmol), (1R,2R)-2-aminocyclohexanol (0.19 g, 1.6 mmol),DIEA (0.71 g, 5.5 mmol) and NMP (2 mL) was heated at 130° C. for 12 h.The reaction mixture was cooled to rt, diluted with EtOAc (30 mL) andwashed with water (10 mL×2). The organic layer was separated, dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by silica gel flash chromatography eluting with 3% MeOH inDCM to afford(1R,2R)-2-((6-((5,6-difluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(65 mg, 30%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.48 (s, 1H),7.97 (d, J=7.5 Hz, 1H), 7.69-7.78 (m, 3H), 7.30 (d, J=8.1 Hz, 1H), 7.22(d, J=8.1 Hz, 1H), 5.44 (s, 2H), 4.74 (d, J=4.8 Hz, 1H), 3.51 (m, 1H),3.42 (m, 1H), 2.00 (m, 1H), 1.87 (m, 1H), 1.58-1.60 (m, 2H), 1.15-1.25(m, 4H); LCMS (ESI) m/z 415 (M+H)⁺.

Example 129(1R,2R)-2-((6-((5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1:4-Fluoro-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroaniline(0.88 g, 66%) was obtained as a yellow solid using a procedure analogousto that described in Step 1 of Example 127, substituting4-fluoro-2-nitroaniline for 4-methyl-2-nitroaniline used in Example 127.¹H NMR (300 MHz, CDCl₃) δ 8.37 (br s, 1H), 8.01 (s, 1H), 7.92 (dd,J=9.0, 3.0 Hz, 1H), 7.85 (d, J=9.0 Hz, 1H), 7.37 (dd, J=8.4, 1.5 Hz,1H), 7.17 (m, 1H), 6.75 (dd, J=9.6, 4.8 Hz, 1H), 4.64 (d, J=5.7 Hz, 2H),3.78 (s, 3H); LCMS (ESI) m/z 350 (M+H)⁺.

Step 2: To a stirred mixture of4-fluoro-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroaniline(1.18 g, 3.3 mmol) from the previous step, acetic acid (3 mL), MeOH (3mL) and DCM (20 mL) at −10° C. was added portionwise zinc dust (1.7 g,26 mmol). The reaction mixture was stirred at −10° C. for 0.5 h. Themixture was poured into ice-water and extracted with EtOAc (100 mL×3).The combined organic layers were washed sequentially with water,saturated aq NaHCO₃ (100 mL×2), and brine (100 mL). The organic layerwas separated, dried over Na₂SO₄, filtered, and concentrated underreduced pressure to afford4-fluoro-N¹-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine(0.93 g, yield 87%) as a yellow solid, which was not purified further.¹H NMR (300 MHz, CDCl₃) δ 7.82 (d, J=8.4 Hz, 1H), 7.76 (s, 1H), 7.42(dd, J=8.4, 1.8 Hz, 1H), 6.42-6.56 (m, 3H), 4.35 (s, 2H), 3.60 (br s,2H), 2.79 (s, 3H); LCMS (ESI) m/z 320 (M+H)⁺.

Step 3: A stirred mixture of4-fluoro-N¹-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine(0.93 g, 2.93 mmol) from the previous step, formic acid (0.5 mL) andtriethyl orthoformate (5 mL) was heated at 100° C. for 1 h. The reactionmixture was cooled to rt and concentrated under reduced pressure. Theresidue was purified by silica gel flash chromatography eluting with 3%MeOH in DCM to afford6-((5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole(0.64 g, 67%) as a yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 7.99 (s, 1H),7.83 (d, J=8.1 Hz, 1H), 7.47-7.51 (m, 2H), 7.26 (m, 1H), 7.17 (m, 1H),7.00 (dt, J=9.3, 2.4 Hz, 1H), 5.44 (s, 2H), 2.77 (s, 3H); LCMS (ESI) m/z330 (M+H)⁺.

Step 4: To a stirred solution of6-((5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole(0.64 g, 1.9 mmol) from the previous step in DCM (20 mL) at 0° C. wasadded a solution of meta-chloroperbenzoic acid (0.472 g, 2.3 mmol) inDCM (3 mL). The mixture was stirred at 0° C. for 2 h. The solution wasdiluted with EtOAc (100 mL) and washed sequentially with saturated aqNa₂S₂O₃, saturated aq NaHCO₃, and brine. The organic layer wasseparated, dried over Na₂SO₄, filtered, and concentrated under reducedpressure to afford6-((5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole(0.63 g, 94%) as a yellow solid, which was not purified further. ¹H NMR(300 MHz, CDCl₃) δ 8.02-8.05 (m, 2H), 7.78 (s, 1H), 7.51 (dd, J=9.6, 2.4Hz, 1H), 7.38 (dd, J=8.4, 1.8 Hz, 1H), 7.20 (m, 1H), 7.00 (dt, J=9.0,2.4 Hz, 1H), 5.52 (s, 2H), 3.07 (s, 3H); LCMS (ESI) m/z 346 (M+H)⁺.

Step 5: A stirred mixture of6-((5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole(0.20 g, 0.57 mmol) from the previous step, (1R,2R)-2-aminocyclohexanol(0.20 g, 1.7 mmol), DIEA (0.73 g, 5.7 mmol) and NMP (2 mL), was heatedat 130° C. for 12 h. The reaction mixture was cooled to rt, diluted withEtOAc (30 mL), and washed with water (10 mL×2). The organic layer wasseparated, dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by silica gel flash chromatographyeluting with 3% MeOH in DCM to afford(1R,2R)-2-((6-((5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(75 mg, 33%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.45 (s, 1H),7.93 (d, J=7.2 Hz, 1H), 7.65 (d, J=1.5 Hz, 1H), 7.56 (m, 1H), 7.43 (dd,J=9.6, 2.4 Hz, 1H), 7.28 (m, 1H), 7.19 (dd, J=8.4, 1.8 Hz, 1H), 7.08(dt, J=9.6, 3.0 Hz, 1H), 5.46 (s, 2H), 4.69 (d, J=5.4 Hz, 1H), 3.51 (m,1H), 3.37 (m, 1H), 2.01 (m, 1H), 1.87 (m, 1H), 1.59-1.63 (m, 2H),1.15-1.23 (m, 4H); LCMS (ESI) m/z 397 (M+H)⁺.

Example 130 Preparation of(1R,2R)-2-((6-((5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1:N-((2-(Methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitro-4-(trifluoromethyl)aniline(0.38 g, 49%) was obtained as a yellow solid using a procedure analogousto that described in Step 1 of Example 127, substituting2-nitro-4-(trifluoromethyl)aniline for 4-methyl-2-nitroaniline used inExample 127. ¹H NMR (300 MHz, CDCl₃) δ 8.64 (br s, 1H), 8.50 (s, 1H),7.87 (d, J=8.4 Hz, 1H), 7.71 (s, 1H), 7.56 (dd, J=9.0, 2.1 Hz, 1H), 7.38(dd, J=8.4, 1.8 Hz, 1H), 6.90 (d, J=9.0 Hz, 1H), 4.69 (d, J=5.7 Hz, 2H),2.79 (s, 3H); LCMS (ESI) m/z 400 (M+H)⁺.

Step 2: A mixture ofN-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitro-4-trifluoromethyl)aniline(0.38 g, 2.0 mmol) from the previous step, MeOH (30 mL) and palladium onactivated charcoal (50 mg) was stirred under hydrogen (1 atm) at rt for12 h. The mixture was filtered to remove the catalyst and the filtratewas concentrated under reduced pressure to affordN¹-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-4-(trifluoromethyl)benzene-1,2-diamine(0.32 g, 91%) as a brown solid, which was not purified further. LCMS(ESI) m/z 370 (M+H)⁺.

Step 3: A stirred mixture ofN¹-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-4-(trifluoromethyl)benzene-1,2-diamine(0.32 g, 0.86 mmol) from the previous step, formic acid (0.5 mL) andtriethyl orthoformate (5 mL) was heated at 100° C. for 1 h. The reactionmixture was cooled to rt and concentrated under reduced pressure. Theresidue was purified by silica gel flash chromatography eluting with 3%MeOH in DCM to afford2-(methylthio)-6-((5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole(0.22 g, 69%) as a yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.12 (s, 1H),8.08 (s, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.48-7.54 (m, 2H), 7.36 (d, J=8.4Hz, 1H), 7.26 (m, 1H), 5.49 (s, 2H), 2.78 (s, 3H); LCMS (ESI) m/z 380(M+H)⁺.

Step 4: To a stirred solution of2-(methylthio)-6-((5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole(0.22 g, 0.58 mmol) from the previous step in DCM (20 mL) at 0° C. wasadded a solution of meta-chloroperbenzoic acid (0.30 g, 1.5 mmol) in DCM(3 mL). The mixture was stirred at 0° C. for 2 h. The mixture wasdiluted with EtOAc (100 mL) and washed sequentially with saturated aqNa₂S₂O₃, saturated aq NaHCO₃, and brine. The organic layer wasseparated, dried over Na₂SO₄, filtered, and concentrated under reducedpressure to afford 2-(methylsulfinyl)-6-((5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole(0.22 g, 96%) as a yellow solid, which was not purified further. ¹H NMR(300 MHz, CDCl₃) δ 8.12-8.14 (m, 2H), 8.05 (d, J=8.4 Hz, 1H), 7.79 (s,1H), 7.50 (dd, J=8.7, 1.2 Hz, 1H), 7.37 (t, J=8.4 Hz, 2H), 5.57 (s, 2H),3.06 (s, 3H); LCMS (ESI) m/z 396 (M+H)⁺.

Step 5: A stirred mixture of2-(methylsulfinyl)-6-((5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole(0.20 g, 0.50 mmol) from the previous step, (1R,2R)-2-aminocyclohexanol(0.17 g, 1.5 mmol), DIEA (0.59 g, 4.6 mmol) and NMP (2 mL) was heated at130° C. for 12 h. The reaction mixture was cooled to rt, diluted withEtOAc (30 mL), and washed with water (10 mL×2). The organic layer wasseparated, dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by silica gel flash chromatographyeluting with 3% MeOH in DCM to afford(1R,2R)-2-((6-((5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(54 mg, 23%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.62 (s, 1H),8.02 (s, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.67 (d,J=1.2 Hz, 1H), 7.54 (d, J=8.7 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.20 (d,J=8.4 Hz, 1H), 5.54 (s, 2H), 4.71 (d, J=5.1 Hz, 1H), 3.51 (m, 1H), 3.39(m, 1H), 2.01 (m, 1H), 1.80 (m, 1H), 1.59-1.62 (m, 2H), 1.17-1.23 (m,4H); LCMS (ESI) m/z 447 (M+H)⁺.

Example 131 Preparation of(1R,2R)-2-((6-(imidazo[1,2-b]pyridazin-3-ylmethyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: A stirred mixture of2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal (500 mg, 1.8mmol) from Step 4 of Example 117 and pyridazin-3-amine (350 mg, 3.6mmol) in 1-butanol (20 mL) was heated at reflux for 15 h. The mixturewas cooled to rt and water (40 mL) was added. The mixture was extractedwith EtOAc (20 mL×3) and the combined organic layers were washed withbrine. The organic layer was separated, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by silicagel flash chromatography eluting with 2 to 5% MeOH in DCM to afford6-(imidazo[1,2-b]pyridazin-3-ylmethyl)-2-(methylthio)benzo[d]thiazole(460 mg, 80%) as a light brown solid. ¹H NMR (300 MHz, CDCl₃) δ 8.32(dd, J=4.5, 1.5 Hz, 1H), 7.94 (dd, J=9.3, 1.5 Hz, 1H), 7.79 (d, J=8.7Hz, 1H), 7.66 (s, 1H), 7.58 (s, 1H), 7.36 (dd, J=8.4, 1.8 Hz, 1H), 7.02(m, 1H), 4.45 (s, 2H), 2.77 (s, 3H); LCMS (ESI) m/z 313 (M+H)⁺.

Step 2: To a stirred solution of6-(imidazo[1,2-b]pyridazin-3-ylmethyl)-2-(methylthio)benzo[d]thiazole(350 mg, 1.1 mmol) from the previous step in DCM (30 mL) at 0° C. wasadded meta-chloroperbenzoic acid (194 mg, 1.1 mmol). The reactionmixture was stirred at 0° C. for 2 h. To the mixture was added saturatedaq Na₂S₂O₃ (15 mL) and the mixture was stirred for a further 0.5 h. Theorganic layer was separated, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by silicagel flash chromatography eluting with 2 to 5% MeOH in DCM to afford6-(imidazo[1,2-b]pyridazin-3-ylmethyl)-2-(methylsulfinyl)benzo[d]thiazole(320 mg, 87%) as a yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.33 (dd,J=4.5, 1.5 Hz, 1H), 7.91-8.00 (m, 3H), 7.62 (s, 1H), 7.54 (dd, J=8.4,1.8 Hz, 1H), 7.03 (m, 1H), 4.52 (s, 2H), 3.05 (s, 3H); LCMS (ESI) m/z329 (M+H)⁺.

Step 3: A stirred mixture of6-(imidazo[1,2-b]pyridazin-3-ylmethyl)-2-(methylsulfinyl)benzo[d]thiazole(260 mg, 0.79 mmol) from the previous step, (1R,2R)-2-aminocyclohexanolhydrochloride (360 mg, 2.38 mmol), DIEA (408 mg, 3.16 mmol) and NMP (10mL), was heated at 140° C. for 48 h. The mixture was cooled to rt andwater (50 mL) was added. The mixture was extracted with EtOAc (30 mL×3)and the combined organic layers were washed with brine. The organiclayer was separated, dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by silica gel flashchromatography eluting with 2 to 10% MeOH in DCM to afford a solid. Thesolid was further purified by recrystallization from a 10:1 mixture ofDCM: MeOH to afford(1R,2R)-2-((6-(imidazo[1,2-b]pyridazin-3-ylmethyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(80 mg, 27%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.53 (dd,J=4.5, 1.5 Hz, 1H), 8.10 (dd, J=9.3, 1.5 Hz, 1H), 7.83 (d, J=7.8 Hz,1H), 7.60 (s, 1H), 7.53 (s, 1H), 7.25 (d, J=8.7 Hz, 1H), 7.19 (m, 1H),7.12 (dd, J=8.4, 1.8 Hz, 1H), 4.71 (d, J=4.8 Hz, 1H), 4.32 (s, 2H), 3.51(m, 1H), 3.38 (m, 1H), 2.04 (m, 1H), 1.88 (m, 1H), 1.59-1.65 (m, 2H),1.16-1.30 (m, 4H); LCMS (ESI) m/z 380 (M+H)⁺.

Example 132 Preparation of(1R,2R)-2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol

Step 1: To a stirred solution of 6-fluoro-3H-imidazo[4,5-b]pyridine (502mg, 3.66 mmol) from Step 2 of Example 70 in anhydrous DMF (10 mL) at 0°C. was added in one portion sodium hydride (60% dispersion in mineraloil, 220 mg, 5.49 mmol), and the mixture was stirred at 0° C. for 30min. To the reaction mixture was added a solution of6-(chloromethyl)-2-(methylthio)benzo[d]oxazole (858 mg, 4.03 mmol) fromStep 3 of Example 56 in DMF (2 mL). The mixture was allowed to warm tort and stir for a further 3 h. To the reaction mixture was added waterand the mixture was extracted with ethyl acetate (3×100 mL). Thecombined organic layers were washed sequentially with water and brine,dried over MgSO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by silica gel flash chromatography eluting with 30to 50% ethyl acetate in petroleum ether to afford6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]oxazole(698 mg, 61%) as a white solid. The regiochemistry of the alkylation wasdetermined by 2-dimensional nuclear Overhauser effect (NOE) experiment.¹H NMR (300 MHz, DMSO-d₆): δ 8.71 (s, 1H), 8.41 (s, 1H), 8.07 (d, J=6.9Hz, 1H), 7.68 (s, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.35 (d, J=6.3 Hz, 1H),5.59 (s, 2H), 2.73 (s, 3H); LCMS (ESI) m/z 315 (M+H)⁺.

Step 2: To a stirred solution of6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]oxazole(595 mg, 1.89 mmol) from the previous step in DCM (10 mL) at 0° C. wasadded 70% meta-chloroperbenzoic acid (425 mg, 2.46 mmol). The reactionmixture was stirred at 0° C. for 2 h. The reaction mixture was washedsequentially with aq sodium sulfite and brine. The organic layer wasseparated, dried over sodium sulfate, filtered, and concentrated underreduced pressure. The residue was purified by silica gel flashchromatography eluting with 50% ethyl acetate in petroleum ether toafford6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole(509 mg, 82%). ¹H NMR (300 MHz, DMSO-d₆): δ 8.73 (s, 1H), 8.40 (s, 2H),7.53 (d, J=7.2 Hz, 1H), 7.37 (s, 1H), 7.15 (d, J=4.5 Hz, 1H), 5.69 (s,2H), 3.18 (s, 3H); LCMS (ESI) m/z 331 (M+H)⁺.

Step 3: A stirred mixture of6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole (220 mg, 0.67 mmol) from the previous step,(1R,2R)-2-amino-cyclohexanol (152 mg, 1 mmol), and DIEA (259 mg, 2.01mmol) in DMA (5 mL) was heated at 135° C. for 2 h. The reaction mixturewas cooled to rt, poured into water (30 mL), and extracted with ethylacetate (50 mL×3). The combined organic layers were washed sequentiallywith water and brine. The organic layer was separated, dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas purified directly by preparative reverse-phase HPLC to afford(1R,2R)-2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol(68 mg, 27%) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆): δ 8.67 (s,1H), 8.41 (m, 1H), 8.06 (m, 1H), 7.79 (m, 1H), 7.39 (s, 1H), 7.13-7.15(m, 2H), 5.48 (s, 2H), 4.67 (d, J=3.9 Hz, 1H), 3.30-3.35 (m, 2H),1.86-1.95 (m, 2H), 1.60-1.65 (m, 2H), 1.15-1.35 (m, 4H); LCMS (ESI) m/z382 (M+H)⁺.

Example 133 Preparation of((1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)methanol

Step 1: To a stirred solution of (1R,2R)-2-aminocyclohexanecarboxylicacid (500 mg, 3.49 mmol) in anhydrous THF (3 mL) at 0° C. was addeddropwise a solution of LAH (2M solution in THF, 7 mL, 13.99 mmol). Thereaction vessel was sealed and the mixture was stirred at 85° C. for 24h. The mixture was cooled to 0° C. and diluted with THF (6 mL). To thereaction mixture was added sequentially water (0.5 mL), 1M aq NaOH (0.5mL), and water (1.5 mL). To the mixture was added MgSO₄ and the mixturewas stirred at rt for 10 min. The mixture was then diluted with THF (10mL) and filtered, and the filtrate was concentrated under reducedpressure to afford ((1R,2R)-2-aminocyclohexyl)methanol (326 mg, 70%) asan oil. ¹H NMR (300 MHz, DMSO-d₆) δ 3.27-3.52 (m, 3H), 2.29 (dt, J=10.1,4.0 Hz, 1H), 1.53-1.78 (m, 4H), 0.98-1.21 (m, 4H), 0.87 (m, 1H).

Step 2:((1R,2R)-2-((6-((6-Bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)methanol(18 mg, 18%) was obtained as a solid using a procedure analogous to thatdescribed in Step 5 of Example 70, substituting6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazolefrom Step 4 of Example 29 for6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazoleused in Example 70, and substituting ((1R,2R)-2-aminocyclohexyl)methanolfrom Step 1 of this Example for (1R,2R)-2-aminocyclohexanol used inExample 70. ¹H NMR (500 MHz, DMSO-d₆) δ 8.65 (s, 1H), 8.48 (d, J=2.0 Hz,1H), 8.39 (d, J=2.0 Hz, 1H), 8.00 (d, J=8.4 Hz, 1H), 7.65 (d, J=1.0 Hz,1H), 7.28 (m, 1H), 7.22 (m, 1H), 5.47 (s, 2H), 4.46 (t, J=5.4 Hz, 1H),3.55 (br m, 1H), 3.41 (m, 1H), 3.30 (m, 1H), 1.98 (d, J=8.9 Hz, 1H),1.83 (d, J=10.8 Hz, 1H), 1.62-1.73 (m, 2H), 1.37 (m, 1H), 1.12-1.29 (m,4H) LCMS (ESI) m/z 472, 474 (M+H)⁺.

Example 134 Preparation of(1R,2R)-2-((6-((6-(1-methyl-1H-tetrazol-5-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

(1R,2R)-2-((6-((6-(1-Methyl-1H-tetrazol-5-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(30 mg, 10%) was obtained as a minor product from the reaction describedin Example 94. The regiochemical assignment was consistent with theresult from a NMR nuclear Overhauser effect (NOE) experiment. ¹H NMR(500 MHz, DMSO-d₆) δ 8.76-8.84 (m, 2H), 8.60 (d, J=2.0 Hz, 1H), 8.00 (d,J=7.4 Hz, 1H), 7.71 (s, 1H), 7.67 (d, J=19.7 Hz, 1H), 7.28-7.35 (m, 2H),7.20-7.28 (m, 2H), 5.56 (s, 3H), 4.77 (br s, 1H), 3.50 (br s, 2H), 2.03(d, J=11.8 Hz, 1H), 1.87 (d, J=11.3 Hz, 1H), 1.52-1.69 (m, 2H),1.08-1.34 (m, 4H). LCMS (ESI) m/z 462 (M+H)⁺.

Example 135 Preparation of(1R,2R)-2-((6-((7-(2-hydroxyethoxy)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

To a stirred solution of(1R,2R)-2-((6-((7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(45 mg, 0.099 mmol) from Example 153 in 2 mL of DCM at −10° C. was addedBBr₃ in DCM (1.0 M, 110 μL, 0.11 mmol). The resulting mixture wasstirred at rt for 30 min before it was cooled to −10° C. and additionalBBr₃ in DCM (1.0 M, 100 μL, 0.10 mmol) was added. After stirring at rtovernight, BBr₃ in DCM (1.0 M, 100 μL, 0.10 mmol) was added and stirringwas continued for 1 d. The resulting mixture was quenched with MeOH andthe mixture was purified by reverse-phase preparative HPLC using amixture of water (5% CH₃CN, 0.05% HCOOH) and CH₃CN (0.05% HCOOH) as themobile phase and Varian Pursuit XRs C18 column as the stationary phaseto afford(1R,2R)-2-((6-((7-(2-hydroxyethoxy)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(16 mg, 37%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.00 (d, J=7.9 Hz, 1H), 7.91(d, J=7.4 Hz, 1H), 7.49 (s, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.22 (s, 1H),7.06 (d, J=8.4 Hz, 1H), 6.90 (d, J=2.0 Hz, 1H), 6.57 (dd, J=2.5, 7.4 Hz,1H), 4.79 (br s, 1H), 4.22 (s, 2H), 4.02 (t, J=4.7 Hz, 2H), 3.72 (t,J=4.7 Hz, 2H), 3.50 (br s, 2H), 2.04 (d, J=12.8 Hz, 1H), 1.87 (d, J=11.3Hz, 1H), 1.54-1.68 (m, 2H), 1.10-1.37 (m, 4H). LCMS (ESI) m/z 439(M+H)⁺.

Example 136 Preparation of((1S,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)methanol

Step 1: ((1S,2R)-2-Aminocyclohexyl)methanol (460 mg, 64%) was obtainedas a solid using a procedure analogous to that described in Step 1 ofExample 133, substituting (1S,2R)-2-aminocyclohexanecarboxylic acidhydrochloride for (1R,2R)-2-aminocyclohexanecarboxylic acid used inExample 133. ¹H NMR (500 MHz, DMSO-d₆) δ 3.40 (m, 1H), 3.28 (dd, J=10.6,6.2 Hz, 1H), 3.04 (q, J=3.4 Hz, 1H), 1.44-1.58 (m, 5H), 1.23-1.43 (m,6H), 1.17 (m, 1H).

Step 2:((1S,2R)-2-((6-((6-Bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)methanol(7 mg, 19%) was obtained as a solid using a procedure analogous to thatdescribed in Step 5 of Example 70, substituting6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazolefrom Step 4 of Example 29 for6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazoleused in Example 70, and substituting ((1S,2R)-2-aminocyclohexyl)methanolfrom Step 1 of this Example for (1R,2R)-2-aminocyclohexanol used inExample 70. ¹H NMR (500 MHz, DMSO-d₆) δ 8.66 (s, 1H), 8.48 (d, J=2.0 Hz,1H), 8.39 (d, J=2.0 Hz, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.65 (d, J=1.0 Hz,1H), 7.28 (m, 1H), 7.23 (m, 1H), 5.48 (s, 2H), 4.61 (br s, 1H), 4.23 (brs, 1H), 3.27 (m, 1H), 3.21 (m, 1H), 1.81 (m, 1H), 1.74 (m, 1H), 1.63 (m,1H), 1.39-1.52 (m, 4H), 1.21-1.37 (m, 2H); LCMS (ESI) m/z 472, 474(M+H)⁺.

Example 137 Preparation of(1R,2R)-2-((6-((5,6-dichloro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1:5,6-Dichloro-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3-nitropyridin-2-amine(105 mg) was obtained as an yellow solid using a procedure analogous tothat described in Step 5 of Example 23, substituting2,3,6-trichloro-5-nitropyridine for 2-chloro-6-methoxy-3-nitropyridineused in Example 23. LCMS (ESI) m/z 401, 403, 405 (M+H)⁺.

Step 2:(1R,2R)-2-((6-((5,6-Dichloro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(35 mg, 31%) was obtained using procedures analogous to those describedin Step 6-9 of Example 23, substituting5,6-dichloro-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3-nitropyridin-2-aminefrom Step 1 of this Example for6-methoxy-N²-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyridine-2,3-diamineused in Step 6 of Example 23, and making the analogous substitutions inthe subsequent steps. ¹H NMR (500 MHz, DMSO-d₆) δ 8.69 (s, 1H), 8.52 (s,1H), 7.98 (d, J=7.9 Hz, 1H), 7.63 (s, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.19(d, J=7.9 Hz, 1H), 5.45 (s, 2H), 4.74 (br s, 1H), 3.51 (br s, 1H), 2.03(d, J=11.8 Hz, 1H), 1.86 (br s, 1H), 1.52-1.69 (m, 2H), 1.06-1.34 (m,4H). LCMS (ESI) m/z 448, 450, 452 (M+H)⁺.

Example 138 Preparation of(1R,2R)-2-((6-((5-ethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

A mixture of1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-ol(80 mg, 0.20 mmol) from Example 147, iodoethane (47 mg, 0.30 mmol) andCs₂CO₃ (196 mg, 0.6 mmol) in NMP (3.5 mL) was stirred at rt for 5 h. Themixture was added to water and extracted with DCM. The organic layer wasseparated, washed sequentially with water and brine, dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by reverse-phase preparative HPLC to afford(1R,2R)-2-((6-((5-ethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(35 mg, 42%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.30 (s, 1H),7.96 (d, J=7.5 Hz, 1H), 7.62 (s, 1H), 7.39 (d, J=9.0 Hz, 1H), 7.29 (d,J=8.4 Hz, 1H), 7.14-7.19 (m, 2H), 6.82 (d, J=9.0 Hz, 1H), 5.41 (s, 2H),4.72 (d, J=4.8 Hz, 1H), 3.97-4.04 (m, 2H), 3.43-3.54 (m, 2H), 2.03 (m,1H), 1.87 (m, 1H), 1.60-1.65 (br m, 2H), 1.32 (t, J=13.8 Hz, 3H),1.15-1.24 (m, 4H). LCMS (ESI) m/z 423 (M+H)⁺.

Example 139 Preparation of3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-5,6-dicarbonitrile

3-((2-(((1R,2R)-2-Hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-5,6-dicarbonitrilewas obtained as a white powder (7 mg, 21%) using a procedures analogousto those described in Example 43, substituting(1R,2R)-2-((6-((5,6-dichloro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolfrom Example 137 for(1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolused in Example 43. ¹H NMR (500 MHz, DMSO-d₆) δ 9.10 (s, 1H), 9.03 (s,1H), 8.08 (d, J=7.4 Hz, 1H), 7.66 (s, 1H), 7.27-7.36 (m, 1H), 7.24 (d,J=8.4 Hz, 1H), 5.56 (s, 2H), 4.84 (br s, 1H), 3.46-3.64 (m, 2H), 2.03(d, J=11.8 Hz, 1H), 1.87 (d, J=10.8 Hz, 1H), 1.51-1.70 (m, 2H),1.08-1.39 (m, 4H). LCMS (ESI) m/z 430 (M+H)⁺.

Example 140 Preparation of3-((2-(((1R,2R)-2-(hydroxymethyl)cyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile

3-((2-(((1R,2R)-2-(Hydroxymethyl)cyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrilewas obtained as a solid (18 mg, 19%) using a procedure analogous to thatdescribed in Example 43, substituting((1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)methanolfrom Example 133 for(1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolused in Example 43. ¹H NMR (500 MHz, DMSO-d₆) δ 8.84 (s, 1H), 8.82 (d,J=1.5 Hz, 1H), 8.72 (d, J=1.5 Hz, 1H), 8.01 (d, J=8.4 Hz, 1H), 7.67 (s,1H), 7.28 (m, 1H), 7.24 (m, 1H), 5.53 (s, 2H), 4.46 (br m, 1H), 3.55 (brm, 1H), 3.41 (d, J=9.8 Hz, 1H), 3.30 (m, 1H), 1.98 (m, 1H), 1.83 (d,J=10.8 Hz, 1H), 1.62-1.73 (m, 2H), 1.37 (m, 1H), 1.17-1.27 (m, 4H); LCMS(ESI) m/z 419 (M+H)⁺.

Example 141 Preparation of(1R,2R)-2-((6-((6-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridine-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

To a stirred solution of CuI (14 mg, 0.0053 mmol), K₂CO₃ (102 mg, 0.74mmol), and pyrazole (30 mg, 0.44 mmol) in 2 mL of DMF under argon wasadded(1R,2R)-2-((6-((6-iodo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolfrom Step 2 of Example 96 (150 mg, 0.30 mmol) andtrans-N¹,N²-dimethylcyclohexane-1,2-diamine (21 mg, 0.15 mmol). Thereaction mixture was then heated at 110° C. overnight. The mixture wascooled to rt, diluted with MeOH, and purified by preparative HPLC usinga mixture of water (5% CH₃CN, 0.05% AcOH) and CH₃CN (0.05% AcOH) as themobile phase and Varian Pursuit XRs Diphenyl column as the stationaryphase to afford(1R,2R)-2-((6-((6-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(85 mg, 64%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.92 (d,J=2.0 Hz, 1H), 8.69 (s, 1H), 8.57 (d, J=2.5 Hz, 1H), 8.50 (d, J=2.5 Hz,1H), 7.96 (d, J=7.4 Hz, 1H), 7.79 (s, 1H), 7.68 (s, 1H), 7.29 (s, 1H),7.20-7.27 (m, 1H), 6.58 (s, 1H), 5.52 (s, 2H), 4.74 (br s, 1H), 3.51 (brs, 1H), 2.03 (d, J=12.3 Hz, 1H), 1.80-1.95 (m, 1H), 1.52-1.72 (m, 2H),1.08-1.33 (m, 4H). LCMS (ESI) m/z 446 (M+H)⁺.

Example 142 Preparation of(1R,2R)-2-((6-(imidazo[1,2-b]pyridazin-3-ylmethyl)benzo[d]oxazol-2-yl)amino)cyclohexanol

Step 1: A mixture of 6-iodobenzo[d]oxazol-2(3H)-one (3.2 g, 12.3 mmmol)in 30 mL of toluene was heated with Lawesson's reagent (2.7 g, 6.7 mmol)at 100° C. for 4 h. Solvent was then removed under reduced pressure andthe residue was cooled to rt and dissolved in 20 mL of DMF. To themixture was added K₂CO₃ (8.4 g, 61.2 mmol) and iodomethane (2.27 mL,36.7 mmol). The resulting mixture was stirred at rt overnight and heatedat 55° C. for 1 h. After cooling to rt, the reaction mixture waspartitioned between EtOAc and water, and the organic layer was washedwith brine, dried over Na₂SO₄, filtered, and evaporated under reducedpressure. The residue was purified on by silica gel columnchromatography eluting with 0-25% EtOAc in hexanes to give6-iodo-2-(methylthio)benzo[d]oxazole as a white solid (1.5 g, 42%). LCMS(ESI) m/z 292 (M+H)⁺.

Step 2: Crude 2-chloro-3-(2-(methylthio)benzo[d]oxazol-6-yl)propanal(120 mg) was obtained using procedures analogous to those described inSteps 3-4 of Example 117, substituting6-iodo-2-(methylthio)benzo[d]oxazole from Step 1 of this Example for6-iodo-2-(methylthio)benzo[d]thiazole used in Step 3 of Example 117, andmaking the analogous substitution in Step 4 of Example 117. LCMS (ESI)m/z 256, 258 (M+H)⁺.

Step 3:(1R,2R)-2-((6-(Imidazo[1,2-b]pyridazin-3-ylmethyl)benzo[d]oxazol-2-yl)amino)cyclohexanol(20 mg) was obtained as a tan solid using procedures analogous to thosedescribed in Steps 1-3 of Example 131, substituting2-chloro-3-(2-(methylthio)benzo[d]oxazol-6-yl)propanal from Step 2 ofthis Example for 2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanalused in Step 1 of Example 131, and making the analogous substitutions inSteps 2 and 3 of Example 131. ¹H NMR (500 MHz, DMSO-d₆) δ 8.53 (d, J=3.0Hz, 1H), 8.09 (d, J=9.4 Hz, 1H), 7.74 (d, J=7.4 Hz, 1H), 7.58 (s, 1H),7.25 (s, 1H), 7.19 (dd, J=4.4, 8.9 Hz, 1H), 7.06-7.13 (m, 1H), 7.03 (d,J=7.9 Hz, 1H), 4.74 (br s, 1H), 4.33 (s, 2H), 1.96 (d, J=9.4 Hz, 1H),1.88 (d, J=10.3 Hz, 1H), 1.63 (br s, 2H), 1.23 (d, J=6.4 Hz, 4H). LCMS(ESI) m/z 364 (M+H)⁺.

Example 143 Preparation of3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-N-methylimidazo[1,2-b]pyridazine-6-carboxamide

Step 1: Ethyl3-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-b]pyridazine-6-carboxylate(272 mg, 54%) was obtained as a white solid using a procedure analogousto that described in Step 6 of Example 117, substituting ethyl6-aminopyridazine-3-carboxylate for 2-aminoisonicotinonitrile used inExample 117. LCMS (ESI) m/z 385 (M+H)⁺.

Step 2: Ethyl3-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-b]pyridazine-6-carboxylate(115 mg, 0.3 mmol) was heated with 2 mL of 2.0 M NH₂Me in THF at 85° C.in a sealed tube for 1 h, at 100° C. for 1 h, then at 110° C. overnight.LCMS analysis showed that the reaction was complete. Solvent wasevaporated under reduced pressure, and the residue was dried in a vacuumoven to giveN-methyl-3-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-b]pyridazine-6-carboxamide,which was used directly for the next step. LCMS (ESI) m/z 370 (M+H)⁺.

Step 3:3-((2-(((1R,2R)-2-Hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-N-methylimidazo[1,2-b]pyridazine-6-carboxamide(55 mg, 42%) was obtained as a tan solid using procedures analogous tothose described in Step 5 of Example 3 followed by Step 5 of Example 2,substitutingN-methyl-3-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-b]pyridazine-6-carboxamidefrom Step 2 of this Example for6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazoleused in Example 3, and making the analogous substitution in Step 5 ofExample 2. ¹H NMR (500 MHz, DMSO-d₆) δ 8.83 (d, J=4.9 Hz, 1H), 8.20 (d,J=9.4 Hz, 2H), 7.88 (d, J=7.9 Hz, 1H), 7.60-7.71 (m, 3H), 7.24-7.32 (m,1H), 7.15-7.24 (m, 1H), 4.76 (br s, 1H), 4.44 (s, 2H), 3.51 (br s, 1H),2.89 (d, J=4.4 Hz, 3H), 2.04 (d, J=11.8 Hz, 1H), 1.87 (d, J=11.3 Hz,1H), 1.53-1.72 (m, 2H), 1.09-1.40 (m, 4H). LCMS (ESI) m/z 437 (M+H)⁺.

Example 144 Preparation of(1R,2R)-2-((6-((6-(hydroxymethyl)imidazo[1,2-b]pyridazin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1:(3-((2-(Methylthio)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-b]pyridazin-6-yl)methanol(48 mg, 34%) was obtained as a white solid using a procedure analogousto that described in Step 2 of Example 2, substituting ethyl3-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-b]pyridazine-6-carboxylatefrom Step 1 of Example 143 for ethyl2-bromobenzo[d]thiazole-6-carboxylate used in Example 2. LCMS (ESI) m/z343 (M+H)⁺.

Step 2:(1R,2R)-2-((6-((6-(Hydroxymethyl)imidazo[1,2-b]pyridazin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(15 mg, 26%) was obtained as a yellow powder using procedures analogousto those described in Step 5 of Example 3 followed by Step 5 of Example2, substituting(3-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-b]pyridazin-6-yl)methanolfrom Step 1 of this Example for6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazoleused in Example 3, and making the analogous substitution in Step 5 ofExample 2. ¹H NMR (500 MHz, DMSO-d₆) δ 8.07 (d, J=9.4 Hz, 1H), 7.91 (d,J=7.4 Hz, 1H), 7.55 (s, 1H), 7.50 (s, 1H), 7.21-7.30 (m, 2H), 7.13 (d,J=8.4 Hz, 1H), 4.79 (br s, 1H), 4.60 (s, 2H), 4.28 (s, 2H), 3.50 (br s,2H), 2.04 (d, J=11.8 Hz, 1H), 1.87 (d, J=10.8 Hz, 1H), 1.52-1.70 (m,2H), 1.06-1.36 (m, 4H). LCMS (ESI) m/z 410 (M+H)⁺.

Example 145 Preparation of(1R,2R)-2-((6-((6-(1H-1,2,4-triazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

(1R,2R)-2-((6-((6-(1H-1,2,4-Triazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(48 mg, 45%) was obtained as a yellow powder using a procedure analogousto that described in Example 141, substituting 1,2,4-triazole forpyrazole used in Example 141. ¹H NMR (500 MHz, DMSO-d₆) δ 9.30 (s, 1H),8.89 (d, J=2.0 Hz, 1H), 8.76 (s, 1H), 8.56 (d, J=2.0 Hz, 1H), 8.29 (s,1H), 7.99 (d, J=7.4 Hz, 1H), 7.69 (s, 1H), 7.28-7.34 (m, 1H), 7.17-7.26(m, 1H), 5.54 (s, 2H), 4.76 (br s, 1H), 3.47-3.60 (m, 2H), 2.03 (d,J=11.8 Hz, 1H), 1.86 (m, 1H), 1.52-1.70 (m, 2H), 1.10-1.34 (m, 4H). LCMS(ESI) m/z 447 (M+H)⁺.

Example 146 Preparation of(1R,2R)-2-((6-((6-iodo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

(1R,2R)-2-((6-((6-Iodo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolwas obtained as an off-white solid using procedures analogous to thosedescribed in Steps 4-5 of Example 3 followed by Step 5 of Example 2,substituting 6-iodo-3H-imidazo[4,5-b]pyridine from Step 1 of Example 96for 3H-imidazo[4,5-b]pyridine used in Step 4 of Example 3, and makingthe analogous substitutions in Step 5 of Example 3 and Step 5 of Example2. ¹H NMR (500 MHz, DMSO-d₆) δ 8.59 (s, 1H), 8.56 (s, 1H), 8.49 (s, 1H),8.06 (d, J=7.4 Hz, 1H), 7.64 (s, 1H), 7.23-7.32 (m, 1H), 7.19 (d, J=8.4Hz, 1H), 5.46 (s, 2H), 4.84 (br s, 1H), 3.50 (br s, 2H), 2.03 (d, J=11.8Hz, 1H), 1.86 (d, J=10.8 Hz, 1H), 1.53-1.67 (m, 2H), 1.09-1.36 (m, 4H).LCMS (ESI) m/z 506 (M+H)⁺.

Example 147 Preparation of1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-ol

Step 1: To a stirred mixture of 4-(benzyloxy)-2-nitroaniline (2.0 g, 8.2mmol) in TFA (14 mL) at −15° C. was added sodium triacetoxyborohydride(2.84 g, 12 mmol). Then a solution of2-(methylthio)benzo[d]thiazole-6-carbaldehyde (1.9 g, 9.0 mmol) fromStep 1 of Example 100 in DCM (10 mL) was added dropwise. The reactionmixture was allowed to warm to 0° C. and stir for 2 h. The mixture waspartitioned between DCM and water. The organic layer was separated andwashed sequentially with saturated aq NaHCO₃ and brine. The organiclayer was separated, dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by silica gel flashchromatography eluting with a gradient of 10% EtOAc in petroleum etherto 100% EtOAc to afford4-(benzyloxy)-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroaniline(2.3 g, 64%) as a red-brown solid. ¹H NMR (300 MHz, CDCl₃) δ 8.34 (s,1H), 7.84 (d, J=8.4 Hz, 1H), 7.72-7.77 (m, 2H), 7.33-7.43 (m, 6H), 7.14(m, 1H), 6.76 (d, J=9.6 Hz, 1H), 5.02 (s, 2H), 4.64 (d, J=5.7 Hz, 2H),2.79 (s, 3H); LCMS (ESI) m/z 438 (M+H)⁺.

Step 2: To a mixture of4-(benzyloxy)-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroaniline(2.8 g, 6.42 mmol) from the previous step, HOAc (7.5 mL), MeOH (7.5 mL)and DCM (50 mL) at 0° C. was added portionwise zinc dust (4.25 g, 65.4mmol). The reaction mixture was stirred at 5° C. for 1 h. The mixturewas filtered and the filtrate was diluted with DCM and washedsequentially with water and saturated aq NaHCO₃. The organic layer wasseparated, dried over Na₂SO₄, filtered, and concentrated under reducedpressure to afford4-(benzyloxy)-N¹-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine(2.49 g, 95%) as a light orange solid which was not purified further. ¹HNMR (300 MHz, CDCl₃) δ 7.83 (d, J=8.4 Hz, 1H), 7.77 (s, 1H), 7.26-7.44(m, 7H), 6.59 (d, J=8.4 Hz, 1H), 6.46 (s, 1H), 6.38 (m, 1H), 4.97 (s,2H), 4.34 (s, 2H), 3.54 (br s, 2H), 2.80 (s, 3H). LCMS (ESI) m/z 408(M+H)⁺.

Step 3: A mixture of4-(benzyloxy)-N¹-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine(2.49 g, 6.1 mmol) from the previous step, triethylorthoformate (60 mL),and formic acid (1.22 g) was stirred at 90° C. for 2 h. The reactionmixture was cooled to rt, and then concentrated under reduced pressure.The residue was purified by silica gel flash chromatography eluting witha gradient of 50% EtOAc in petroleum ether to 100% EtOAc to afford6-((5-(benzyloxy)-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole(1.6 g, 62%) as a light yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 7.93 (s,1H), 7.82 (d, J=8.4 Hz, 1H), 7.50 (s, 1H), 7.44-7.49 (m, 2H), 7.30-7.40(m, 4H), 7.26 (m, 1H), 7.13 (d, J=9.0 Hz, 1H), 6.98 (m, 1H), 5.41 (s,2H), 5.10 (s, 2H), 2.77 (s, 3H); LCMS (ESI) m/z 418 (M+H)⁺.

Step 4: A mixture of6-((5-(benzyloxy)-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole(1.6 g, 3.8 mmol) from the previous step and meta-chloroperbenzoic acid(0.82 g, 4.75 mmol) in DCM (38 mL) was stirred at 0° C. for 2 h. Themixture was diluted with DCM and washed sequentially with aq Na₂S₂O₃,saturated aq NaHCO₃, and water. The organic layer was separated, driedover Na₂SO₄, filtered, and concentrated under reduced pressure to afford6-((5-(benzyloxy)-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole(1.58 g, 96%) as a yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.02 (d,J=8.4 Hz, 1H), 7.96 (s, 1H), 7.76 (s, 1H), 7.44-7.47 (m, 2H), 7.31-7.40(m, 5H), 7.12 (d, J=8.7 Hz, 1H), 6.97 (m, 1H), 5.49 (s, 2H), 5.11 (s,2H), 3.08 (s, 3H); LCMS (ESI) m/z 434 (M+H)⁺.

Step 5: A stirred mixture of6-((5-(benzyloxy)-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole(1.48 g, 3.4 mmol) from the previous step, (1R,2R)-2-aminocyclohexanolhydrochloride (1.29 g, 8.5 mmol), and DIEA (2.19 g, 17 mmol) in DMA (44mL) was heated at 138° C. for 15 h. The reaction mixture was cooled tort and concentrated under reduced pressure. The residue was purified bysilica gel flash chromatography eluting with 2 to 6% MeOH in DCM toafford(1R,2R)-2-((6-((5-(benzyloxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(0.98 g, 59%) as a yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 7.88 (s, 1H),7.43-7.46 (m, 3H), 7.29-7.39 (m, 4H), 7.25 (s, 1H), 7.13-7.16 (m, 2H),6.96 (m, 1H), 5.75 (br s, 1H), 5.31 (s, 2H), 5.09 (s, 2H), 3.46-3.56 (m,2H), 2.07-2.18 (m, 2H), 1.71-1.77 (m, 2H), 1.26-1.40 (m, 4H); LCMS (ESI)m/z 485 (M+H)⁺.

Step 6: To a stirred mixture of(1R,2R)-2-((6-((5-(benzyloxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(3.4 g, 7.02 mmol) in DCM (40 mL) at −30° C. was added boron tribromide(3.4 mL, 35.4 mmol). The reaction mixture was stirred at −30° C. for 2h. To the mixture was added water and the pH was adjusted to 8 with aqNH₄OH. The precipitate was collected by filtration to give a lightyellow solid (2.45 g). A portion of this solid (150 mg) was purifieddirectly by reverse-phase preparative HPLC to afford1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-olas a white solid (54 mg). ¹H NMR (300 MHz, DMSO-d₆) δ 8.98 (s, 1H), 8.22(s, 1H), 7.93 (d, J=7.5 Hz, 1H), 7.61 (s, 1H), 7.30 (s, 1H), 7.27 (s,1H), 7.17 (m, 1H), 6.94 (s, 1H), 6.69 (m, 1H), 5.37 (s, 2H), 4.71 (d,J=5.4 Hz, 1H), 3.53 (m, 1H), 3.36 (m, 1H), 2.03 (m, 1H), 1.88 (m, 1H),1.60-1.63 (m, 2H), 1.15-1.29 (m, 4H). LCMS (ESI) m/z 395 (M+H)⁺.

Example 148 Preparation of(1R,2R)-2-((6-((5,7-difluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1:2,4-Difluoro-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-6-nitroaniline(0.8 g, 73%) was obtained as a yellow solid using a procedure analogousto that described in Step 1 of Example 127, substituting2,4-difluoro-6-nitroaniline for 4-methyl-2-nitroaniline used in Example127. ¹H NMR (300 MHz, CDCl₃) δ 7.84 (d, J=8.1 Hz, 1H), 7.70-7.74 (m,2H), 7.36 (dd, J=8.4, 1.8 Hz, 1H), 7.05 (m, 1H), 4.78 (d, J=3.6 Hz, 2H),2.79 (s, 3H); LCMS (ESI) m/z 368 (M+H)⁺.

Step 2:4,6-Difluoro-N¹-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine(0.29 g, 91%) was obtained as a yellow solid using a procedure analogousto that described in Step 2 of Example 130, substituting2,4-difluoro-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-6-nitroanilinefrom Step 1 of this Example forN-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitro-4-trifluoromethyl)anilineused in Example 130. ¹H NMR (300 MHz, CDCl₃) δ 7.79 (d, J=8.4 Hz, 1H),7.70 (s, 1H), 7.35 (dd, J=8.7, 1.8 Hz, 1H), 6.18-6.24 (m, 2H), 4.20 (brs, 2H), 4.13 (s, 2H), 2.79 (s, 3H); LCMS (ESI) m/z 338 (M+H)⁺.

Step 3:6-((5,7-Difluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole(0.18 g, 59%) was obtained as a yellow solid using a procedure analogousto that described in Step 3 of Example 130, substituting4,6-difluoro-N⁴-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diaminefrom Step 2 of this Example forN¹-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-4-(trifluoromethyl)benzene-1,2-diamineused in Example 130. LCMS (ESI) m/z 348 (M+H)⁺.

Step 4:6-((5,7-Difluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole(0.17 g, 90%) was obtained as a yellow solid using a procedure analogousto that described in Step 4 of Example 130, substituting6-((5,7-difluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazolefrom Step 3 of this Example for2-(methylthio)-6-((5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazoleused in Example 130. ¹H NMR (300 MHz, CDCl₃) δ 8.01-8.05 (m, 2H), 7.81(s, 1H), 7.41 (dd, J=8.7, 1.8 Hz, 1H), 7.32 (dd, J=9.0, 2.1 Hz, 1H),6.80 (t, J=9.6 Hz, 1H), 5.64 (s, 2H), 3.06 (s, 3H); LCMS (ESI) m/z 364(M+H)⁺.

Step 5:((1R,2R)-2-((6-((5,7-Difluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(65 mg, 34.5%) was obtained as a yellow solid using a procedureanalogous to that described in Step 5 of Example 130, substituting6-((5,7-difluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazolefrom Step 4 of this Example for2-(methylsulfinyl)-6-((5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazoleused in Example 130. ¹H NMR (300 MHz, DMSO-d₆) δ 8.51 (s, 1H), 7.95 (d,J=7.8 Hz, 1H), 7.54 (s, 1H), 7.36 (dd, J=9.3, 1.5 Hz, 1H), 7.30 (d,J=8.1 Hz, 1H), 7.06-7.15 (m, 2H), 5.51 (s, 2H), 4.71 (d, J=5.1 Hz, 1H),3.53 (m, 1H), 3.33 (m, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.59-1.63 (m,2H), 1.14-1.29 (m, 4H); LCMS (ESI) m/z 415 (M+H)⁺.

Example 149 Preparation of(1R,2R)-2-((6-((5-(trifluoromethoxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1:N-((2-(Methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitro-4-(trifluoromethoxy)aniline(0.85 g, 51%) was obtained as a yellow solid using a procedure analogousto that described in Step 1 of Example 127, substituting2-nitro-4-(trifluoromethoxy)aniline for 4-methyl-2-nitroaniline used inExample 127. ¹H NMR (300 MHz, CDCl₃) δ 8.49 (br s, 1H), 8.28 (d, J=0.6Hz, 1H), 7.94 (d, J=3.0 Hz, 1H), 7.84 (s, 1H), 7.38 (dd, J=8.4, 1.5 Hz,1H), 7.29 (m, 1H), 6.83 (d, J=9.0 Hz, 1H), 4.66 (d, J=5.7 Hz, 2H), 2.79(s, 3H); LCMS (ESI) m/z 416 (M+H)⁺.

Step 2:N-((2-(Methylthio)benzo[d]thiazol-6-yl)methyl)-4-(trifluoromethoxy)benzene-1,2-diamine(0.69 g, 88%) was obtained as a yellow solid using a procedure analogousto that described in Step 2 of Example 130, substitutingN-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitro-4-(trifluoromethoxy)anilinefrom Step 1 of this Example forN-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitro-4-trifluoromethyl)anilineused in Example 130. ¹H NMR (300 MHz, CDCl₃) δ 7.83 (d, J=8.4 Hz, 1H),7.75 (s, 1H), 7.41 (dd, J=8.4, 1.5 Hz, 1H), 6.54-6.65 (m, 4H), 4.35 (s,2H), 3.48 (br s, 2H), 2.77 (s, 3H); LCMS (ESI) m/z 386 (M+H)⁺.

Step 3:2-(Methylthio)-6-((5-(trifluoromethoxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole(0.55 g, 79%) was obtained as a yellow solid using a procedure analogousto that described in Step 3 of Example 130, substitutingN¹-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-4-(trifluoromethoxy)benzene-1,2-diaminefrom Step 2 of this Example forN¹-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-4-(trifluoromethyl)benzene-1,2-diamineused in Example 130. ¹H NMR (300 MHz, CDCl₃) δ 8.03 (s, 1H), 7.83 (d,J=8.4 Hz, 1H), 7.70 (s, 1H), 7.52 (s, 1H), 7.22-7.28 (m, 2H), 7.13 (m,1H), 5.45 (s, 2H), 2.78 (s, 3H); LCMS (ESI) m/z 396 (M+H)⁺.

Step 4:2-(Methylsulfinyl)-6-((5-(trifluoromethoxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole(0.55 g, 96%) was obtained as a yellow solid using a procedure analogousto that described in Step 4 of Example 130, substituting2-(methylthio)-6-((5-(trifluoromethoxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazolefrom Step 3 of this Example for2-(methylthio)-6-((5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazoleused in Example 130. ¹H NMR (300 MHz, CDCl₃) δ 8.08 (s, 1H), 7.04 (d,J=8.4 Hz, 1H), 7.79 (s, 1H), 7.71 (s, 1H), 7.38 (dd, J=8.4, 1.8 Hz, 1H),7.24 (m, 1H), 7.13 (m, 1H), 5.52 (s, 2H), 3.06 (s, 3H); LCMS (ESI) m/z412 (M+H)⁺.

Step 5:(1R,2R)-2-((6-((5-(Trifluoromethoxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(65 mg, 35%) was obtained as a white solid using a procedure analogousto that described in Step 5 of Example 130, substituting 2-(methylsulfinyl)-6-((5-(trifluoromethoxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazolefrom Step 4 of this Example for2-(methylsulfinyl)-6-((5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazoleused in Example 130. ¹H NMR (300 MHz, DMSO-d₆) δ 8.54 (s, 1H), 7.93 (d,J=6.6 Hz, 1H), 7.65-7.75 (m, 3H), 7.30 (d, J=8.1 Hz, 1H), 7.21-7.26 (m,2H), 5.50 (s, 2H), 4.69 (d, J=5.1 Hz, 1H), 3.51 (m, 1H), 3.40 (m, 1H),2.01 (m, 1H), 1.85 (m, 1H), 1.57-1.60 (m, 2H), 1.20-1.23 (m, 4H); LCMS(ESI) m/z 463 (M+H)⁺.

Example 150 Preparation of(1R,2R)-2-((6-((6-methoxyimidazo[1,2-b]pyridazin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: A stirred mixture of2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal from Step 4 ofExample 117 (600 mg, 2.2 mmol) and 6-methoxypyridazin-3-amine (550 mg,4.4 mmol) in 1-butanol (20 mL) was heated at reflux overnight. Themixture was cooled to rt and water (40 mL) was added. The mixture wasextracted with EtOAc (20 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by silica gel chromatography elutingwith 50:1 to 20:1 DCM/MeOH to afford6-((6-methoxyimidazo[1,2-b]pyridazin-3-yl)methyl)-2-(methylthio)benzo[d]thiazoleas a light brown solid (500 mg, 66%). ¹H NMR (300 MHz, CDCl₃) δ7.79-7.73 (m, 2H), 7.67 (d, J=1.2 Hz, 1H), 7.43 (s, 1H), 7.38 (dd,J=1.5, 8.4 Hz, 1H), 6.64 (d, J=9.6 Hz, 1H), 4.33 (s, 2H), 3.94 (s, 3H),2.78 (s, 3H). LCMS (ESI) m/z 343 (M+H)⁺.

Step 2: To a solution of6-((6-methoxyimidazo[1,2-b]pyridazin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole(500 mg, 1.46 mmol) in DCM (30 mL) was added m-CPBA (314 mg, 1.82 mmol)at 0° C. The reaction mixture was stirred for 2 h at 0° C., then aqNa₂SO₃ (15 mL) was added and the mixture was stirred for 0.5 h. Theorganic layer was separated, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography eluting with 50:1 to 20:1 DCM/MeOH to afford6-((6-methoxyimidazo[1,2-b]pyridazin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazoleas a yellow solid (500 mg, 95%). ¹H NMR (300 MHz, CDCl₃) δ 7.99-7.93 (m,2H), 7.76 (d, J=9.6 Hz, 1H), 7.53 (dd, J=1.5, 8.4 Hz, 1H), 7.46 (s, 1H),6.65 (d, J=9.3 Hz, 1H), 4.42 (s, 2H), 3.94 (s, 3H), 3.06 (s, 3H). LCMS(ESI) m/z 359 (M+H)⁺.

Step 3: A mixture of6-((6-methoxyimidazo[1,2-b]pyridazin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole(320 mg, 0.89 mmol), (1R,2R)-2-amino cyclohexanol (308 mg, 2.68 mmol)and DIEA (231 mg, 1.79 mmol) in NMP (11 mL) was stirred for 1 d at 140°C. The mixture was cooled to rt and water (50 mL) was added. The mixturewas extracted with EtOAc (30 mL×3). The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by silica gel chromatographyeluting with 50:1 to 10:1 DCM/MeOH, then further purified by preparativeHPLC to afford(1R,2R)-2-((6-((6-methoxyimidazo[1,2-b]pyridazin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolas a brown solid (120 mg, 33%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.97 (d,J=9.6 Hz, 1H), 7.83 (d, J=7.5 Hz, 1H), 7.61 (s, 1H), 7.44 (s, 1H), 7.26(d, J=8.4 Hz, 1H), 7.18 (d, J=9.9 Hz, 1H), 6.82 (d, J=9.6 Hz, 1H), 4.72(d, J=5.4 Hz, 1H), 4.23 (s, 2H), 3.95 (s, 3H), 3.52-3.49 (m, 1H),3.39-3.36 (m, 1H), 2.05-2.01 (m, 1H), 1.90-1.86 (m, 1H), 1.65-1.59 (m,2H), 1.28-1.14 (m, 4H). LCMS (ESI) m/z 410 (M+H)⁺.

Example 151 Preparation of(1R,2R)-2-((6-((5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol

Step 1: To a solution of 4-methoxy-2-nitroaniline (500 mg, 2.99 mmol)and TFA (3.07 mL) in DCM (15 mL) at 5° C. was added NaBH(OAc)₃ (1.9 g,8.97 mmol). To the resulting mixture at 0° C. was added a solution of2-(methylthio)benzo[d]oxazole-6-carbaldehyde (630 mg, 3.29 mmol) in DCM(10 mL), and. the mixture was stirred at 0° C. for 2 h. The reactionmixture was diluted with DCM and washed sequentially with H₂O, aq NaHCO₃and brine. The organic layer was dried over Na₂SO₄ and concentratedunder reduced pressure to give4-methoxy-N-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)-2-nitroanilineas a light brown solid (1.08 g, quantitative). ¹H NMR (300 MHz, DMSO-d₆)δ 8.62 (t, 1H), 7.64 (s, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.52 (s, 1H), 7.37(d, J=9.3 Hz, 1H), 7.18 (d, J=6.0 Hz, 1H), 6.93 (d, J=9.3 Hz, 1H), 4.71(d, J=5.7 Hz, 1H), 3.72 (s, 3H), 2.75 (s, 3H). LCMS (ESI) m/z 346(M+H)⁺.

Step 2: To a stirred solution of4-methoxy-N-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)-2-nitroaniline(1.07 g, 3.11 mmol), HOAc (3.7 mL) and MeOH (3.7 mL) in DCM (40 mL) at0° C. was added zinc dust (2.02 g, 31.1 mmol) portionwise. Afterstirring for 2 h, the mixture was filtered. The filtrate was washed withaq NaHCO₃ and brine, dried over Na₂SO₄ and concentrated under reducedpressure to give4-methoxy-N¹-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)benzene-1,2-diamine(775 mg, 79.1%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.60 (s, 1H), 7.55 (d,J=8.4 Hz, 1H), 7.35 (d, J=9.6 Hz, 1H), 6.26 (d, J=8.1 Hz, 1H), 6.21 (s,1H), 5.97 (d, J=9.0 Hz, 2H), 4.74 (t, 1H), 4.68 (s, 1H), 4.31 (d, J=5.7Hz, 1H), 3.55 (s, 3H), 2.74 (s, 3H). LCMS (ESI) m/z 316 (M+H)⁺.

Step 3: A solution of4-methoxy-N¹-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)benzene-1,2-diamine(755 mg, 2.40 mmol) in triethoxymethane (8 mL) and HCOOH (0.2 mL) wasstirred at 90° C. for 40 min. The reaction mixture was concentratedunder reduced pressure. The residue was purified by silica gelchromatography eluting with 1:2 petroleum ether/ethyl acetate to give6-((5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]oxazoleas a light brown solid (683 mg, 87.6%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.36(s, 1H), 7.66 (s, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.43 (d, J=9.0 Hz, 1H),7.30 (d, J=6.6 Hz, 1H), 7.16 (s, 1H), 6.82 (d, J=6.6 Hz, 1H), 5.54 (s,2H), 3.75 (s, 3H), 2.73 (s, 3H). LCMS (ESI) m/z 326 (M+H)⁺.

Step 4: A solution of6-((5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]oxazole (683 mg, 2.1 mmol) and m-CPBA (471 mg, 2.7 mmol) inDCM (10 mL) was stirred at 0° C. for 3.5 h. The reaction mixture waswashed with aq Na₂S₂O₃ and brine. The organic layer was dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by silica gel chromatography eluting with 1:1 petroleumether/ethyl acetate to give6-((5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole(455 mg, 63.6%) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.40 (s,1H), 7.88 (m, 2H), 7.44 (m, 2H), 7.18 (s, 1H), 6.83 (s, 1H), 5.63 (s,2H), 3.75 (s, 3H), 3.18 (s, 3H). LCMS (ESI) m/z 342 (M+H)⁺.

Step 5: A mixture of6-((5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole (450 mg, 1.32 mmol),(1R,2R)-2-aminocyclohexanol (228 mg, 1.98 mmol) and DIEA (341 mg, 2.64mmol) in DMA (10 mL) was stirred at 120° C. for 1.5 h. The reactionmixture was cooled to rt and poured into water (30 mL) and the resultingmixture was extracted with ethyl acetate (30 mL×3). The combined organiclayers were washed with water and brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified bypreparative HPLC to give(1R,2R)-2-((6-((5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanolas a white solid (155 mg, 29.9%). ¹HNMR (300 MHz, DMSO-d₆) δ 8.32 (s,1H), 7.80 (d, J=7.8 Hz, 1H), 7.41 (d, J=8.7 Hz, 1H), 7.33 (s, 1H),7.16-7.08 (m, 3H), 6.82 (dd, J=2.4, 8.7 Hz, 1H), 5.42 (s, 2H), 4.68 (d,J=4.5 Hz, 1H), 3.75 (s, 3H), 3.35 (br s, 2H), 1.90 (m, 2H), 1.62 (br s,2H), 1.22 (br s, 4H). LCMS (ESI) m/z 393 (M+H)⁺.

Example 152 Preparation of(1R,2R)-2-((6-((6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol

Step 1: To a solution of 5-methoxy-2-nitroaniline (500 mg, 2.99 mmol)and TFA (3.07 mL) in DCM (15 mL) at 5° C. was added NaBH(OAc)₃ (1.9 g,8.97 mmol). To the resulting mixture at 0° C. was added dropwise asolution of 2-(methylthio)benzo[d]oxazole-6-carbaldehyde (630 mg, 3.29mmol) in DCM (10 mL) and. the mixture was stirred at 0° C. for 2 h. Thereaction mixture was diluted with DCM and washed with H₂O, aq NaHCO₃ andbrine. The organic layer was dried over Na₂SO₄ and concentrated underreduced pressure to give5-methoxy-N-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)-2-nitro anilineas a light brown solid (1.06 g, 100%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.90(t, 1H), 8.04 (d, J=8.7 Hz, 1H), 7.68 (s, 1H), 7.60 (d, J=8.4 Hz, 1H),7.41 (d, J=7.5 Hz, 1H), 6.28-6.32 (m, 2H), 4.73 (d, J=6 Hz, 2H), 3.72(s, 3H), 2.74 (s, 3H). LCMS (ESI) m/z 345 (M+H)⁺.

Step 2: To a stirred solution of5-methoxy-N-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)-2-nitroaniline(1.05 g, 3.05 mmol), HOAc (3.6 mL) and methnol (3.6 mL) in DCM (40 mL)at 0° C. was added zinc dust (1.98 g, 30.5 mmol) portionwise. Afterstirring for 2 h, the mixture was filtered. The filtrate was washed withaq NaHCO₃ and brine, dried over Na₂SO₄ and concentrated under reducedpressure to give5-methoxy-N¹-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)benzene-1,2-diamineas a light yellow solid (920 mg, 95.7%). ¹H NMR (300 MHz, DMSO-d₆) δ7.55-7.60 (m, 2H), 7.35 (d, J=7.8 Hz, 1H), 6.47 (d, J=8.1 Hz, 1H),5.93-5.99 (m, 2H), 5.32 (t, 1H), 4.38 (d, J=5.7 Hz, 2H), 4.13 (s, 2H),3.50 (s, 3H), 2.74 (s, 3H). LCMS (ESI) m/z 316 (M+H)⁺.

Step 3: A mixture of5-methoxy-N¹-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)benzene-1,2-diamine(920 mg, 2.92 mmol), triethoxymethane (8.8 mL) and HCOOH (0.2 mL) wasstirred at 90° C. for 40 min. The reaction mixture was concentratedunder reduced pressure. The residue was purified by silica gelchromatography eluting with 1:2 petroleum ether/ethyl acetate to give6-((6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]oxazoleas a light brown solid (799 mg, 84.1%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.28(s, 1H), 7.68 (s, 1H), 7.59 (d, J=8.1 Hz, 1H), 7.52 (d, J=9.0 Hz, 1H),7.33 (d, J=6.6 Hz, 1H), 7.15 (s, 1H), 6.80 (d, J=6.6 Hz, 1H), 5.54 (s,2H), 3.75 (s, 3H), 2.73 (s, 3H). LCMS (ESI) m/z 326 (M+H)⁺.

Step 4: A solution of6-((6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methyl1thio)benzo[d]oxazole (799 mg, 2.46 mmol) and m-CPBA (551 mg, 3.20 mmol)in DCM (18 mL) was stirred at 0° C. for 3.5 h. The reaction mixture waswashed with aqueous Na₂S₂O₃ and brine. The organic layer was dried overNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby silica gel chromatography eluting with 1:1 petroleum ether/ethylacetate to give6-((6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazoleas a light yellow solid (697 mg, 74.9%). ¹H NMR (300 MHz, DMSO-d₆) δ8.34 (s, 1H), 7.87-7.92 (m, 2H), 7.47-7.55 (m, 2H), 7.16 (s, 1H), 6.82(d, J=5.4 Hz, 1H), 5.63 (s, 2H), 3.75 (s, 3H), 3.18 (s, 3H). LCMS (ESI)m/z 342 (M+H)⁺.

Step 5: A mixture of6-((6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole (595 mg, 1.74 mmol),(1R,2R)-2-aminocyclohexanol (301 mg, 2.6 mmol) and DIEA (449 mg, 3.48mmol) in DMA (12 mL) was stirred at 120° C. for 1.5 h. The reactionmixture was cooled to rt, poured into water (30 mL) and extracted withethyl acetate (30 mL×3). The combined organic layers were washed withbrine, dried over Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by preparative HPLC to give(1R,2R)-2-((6-((6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanolas a white solid (198 mg, 29.0%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.24 (s,1H), 7.80 (d, J=6.9 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.36 (s, 1H), 7.14(s, 3H), 6.80 (dd, J=2.4, 9.0 Hz, 1H), 5.42 (s, 2H), 4.68 (d, J=3.3 Hz,1H), 3.76 (s, 3H), 3.33 (br s, 2H), 1.89 (br s, 2H), 1.62 (br s, 2H),1.22 (br s, 4H). LCMS (ESI) m/z 393 (M+H)⁺.

Example 153 Preparation of(1R,2R)-2-((6-((7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: (1R,2R)-2-((6-Iodobenzo[d]thiazol-2-yl)amino)cyclohexanol (1.9g, 81%) was obtained as a yellow solid using procedures analogous tothose described in Step 5 of Example 3 followed by Step 5 of Example 2,substituting 6-iodo-2-(methylthio)benzo[d]thiazole (Ref: US2009/163464A1, 2009) for6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazoleused in Example 3, and then making the analogous substitution in Step 5of Example 2. LCMS (ESI) m/z 375 (M+H)⁺.

Step 2: Crude2-chloro-3-(2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)propanal(180 mg) was obtained as a yellow oil using procedures analogous tothose described in Steps 3-4 of Example 117, substituting(1R,2R)-2-((6-iodobenzo[d]thiazol-2-yl)amino)cyclohexanol from Step 1 ofthis Example for 6-iodo-2-(methylthio)benzo[d]thiazole used in Step 3 ofExample 117, and making the analogous substitution in Step 4 of Example117. LCMS (ESI) m/z 339, 341 (M+H)⁺. In the same reaction,2-chloro-3-(4-chloro-2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)propanalwas also present as a minor product.

Step 3:(1R,2R)-2-((6-((7-(2-Methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(28 mg, 18%) was obtained as a yellow powder using a procedure analogousto that described in Step 6 of Example 117, substituting4-(2-methoxyethoxy)pyridin-2-amine (Ref: WO2008/121687 A2, 2008) for2-aminoisonicotinonitrile, and2-chloro-3-(2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)propanalfrom Step 2 of this Example for2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal used in Example117. ¹H NMR (500 MHz, DMSO-d₆) δ 8.00 (d, J=7.4 Hz, 1H), 7.89 (d, J=7.4Hz, 1H), 7.49 (s, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.23 (s, 1H), 7.06 (d,J=7.9 Hz, 1H), 6.92 (d, J=2.5 Hz, 1H), 6.58 (dd, J=2.5, 7.4 Hz, 1H),4.77 (d, J=5.9 Hz, 1H), 4.22 (s, 2H), 4.07-4.16 (m, 2H), 3.60-3.72 (m,2H), 3.50 (br s, 2H), 3.30 (s, 3H), 2.04 (d, J=12.3 Hz, 1H), 1.87 (d,J=11.8 Hz, 1H), 1.53-1.71 (m, 2H), 1.06-1.36 (m, 4H). LCMS (ESI) m/z 453(M+H)⁺.

Example 154 Preparation of(1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-fluorobenzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: A mixture of 4-amino-2,5-difluorobenzonitrile (1.0 g, 6.5 mmol)and O-ethylxanthic acid potassium salt (1.2 g, 7.8 mmol) in DMF (15 mL)was heated at reflux for 6 h. The mixture was cooled to rt andpartitioned between EtOAc (200 mL) and 1 M aq Na₂CO₃ (100 mL). Theorganic layer was separated and the aqueous layer was extracted withadditional EtOAc (2×200 mL). The combined organic layers were washedwith brine (100 mL), dried over Mg₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by silica gel flashchromatography eluting with 2% MeOH in DCM to afford6-cyano-5-fluorobenzo[d]thiazole-2-thiolate potassium salt (1.94 g) asan orange solid. LCMS (ESI) m/z 211 (M+H)⁺.

Step 2: 5-Fluoro-2-(methylthio)benzo[d]thiazole-6-carbonitrile wassynthesized as an orange solid (1.2 g, 86%) using a procedure analogousto that described in Step 2 of Example 114, substituting6-cyano-5-fluorobenzo[d]thiazole-2-thiolate potassium salt from theprevious step for ethyl 2-mercaptothiazolo[4,5-b]pyridine-6-carboxylatepotassium salt used in Example 114. ¹H NMR (300 MHz, DMSO-d₆) δ 8.67 (d,J=6.4 Hz, 1H), 8.01 (d, J=10.5 Hz, 1H), 2.84 (s, 3H); LCMS (ESI) m/z 225(M+H)⁺.

Step 3: To a stirred mixture of5-fluoro-2-(methylthio)benzo[d]thiazole-6-carbonitrile in anhydrous THF(20 mL) at −20° C. under argon was added dropwise lithium aluminumhydride (2 M solution in THF, 11.7 mL, 5.9 mmol). After 1 h, water (500μL) and 1 M aq NaOH (500 μL) were added slowly to the reaction mixture.After 5 minutes, additional water (2 mL) was added and the mixture wasstirred at rt for 30 minutes. The mixture was filtered and the filtratewas concentrated under reduced pressure. The residue was purified bysilica gel flash chromatography eluting with 5% MeOH in CH₂Cl₂ to afford(5-fluoro-2-(methylthio)benzo[d]thiazol-6-yl)methanamine (128 mg, 29%)as a colorless oil. ¹H NMR (500 MHz, DMSO-d₆) δ 8.07 (d, J=7.1 Hz, 1H),7.64 (d, J=11.1 Hz, 1H), 3.83 (s, 2H), 2.78 (s, 3H), 1.80-2.06 (m, 2H);LCMS (ESI) m/z 229 (M+H)⁺.

Step 4: To a stirred mixture of(5-fluoro-2-(methylthio)benzo[d]thiazol-6-yl)methanamine (128 mg, 0.6mmol) and DIEA (195 μL, 1.2 mmol) at 0° C. under argon was added2-chloro-3-nitropyridine (98 mg, 0.7 mmol) in one portion. The mixturewas stirred at rt for 18 h and then concentrated under reduced pressure.The residue was purified by silica gel flash chromatography eluting witha gradient of 100% hexanes to 50% EtOAc in hexanes to affordN-((5-fluoro-2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3-nitropyridin-2-amine(165 mg, 84%) as a yellow oil. LCMS (ESI) m/z 351 (M+H)⁺.

Step 5:N²-((5-Fluoro-2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyridine-2,3-diaminewas synthesized as a yellow solid (200 mg) using a procedure analogousto that described in Step 2 of Example 41, substitutingN-((5-fluoro-2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3-nitropyridin-2-aminefrom the previous step for4-bromo-5-methoxy-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroanilineused in Example 41. LCMS (ESI) m/z 321 (M+H)⁺.

Step 6:6-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)-5-fluoro-2-(methylthio)benzo[d]thiazolewas synthesized as a tan solid (180 mg) using a procedure analogous tothat described in Step 3 of Example 41, substitutingN²-((5-fluoro-2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyridine-2,3-diaminefrom the previous step for4-bromo-5-methoxy-N¹-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamineused in Example 41. LCMS (ESI) m/z 331 (M+H)⁺.

Step 7: 6-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)-5-fluoro-2-(methylsulfinyl)benzo[d]thiazole was synthesized as a white foam (314 mg) usinga procedure analogous to that described in Step 6 of Example 36,substituting6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-fluoro-2-(methylthio)benzo[d]thiazolefrom the previous step for the6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole usedin Example 36. LCMS (ESI) m/z 347 (M+H)⁺.

Step 8:(1R,2R)-2-((6-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)-5-fluorobenzo[d]thiazol-2-yl)amino)cyclohexanolwas synthesized as a white powder (42 mg, 19%) using a procedureanalogous to that described in Step 7 of Example 36, substituting6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-fluoro-2-(methylsulfinyl)benzo[d]thiazolefrom the previous step for6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazoleused in Example 36. ¹H NMR (500 MHz, DMSO-d₆) δ 8.50 (s, 1H), 8.36 (dd,J=1.2, 4.7 Hz, 1H), 8.15 (d, J=7.6 Hz, 1H), 8.09 (dd, J=1.1, 8.0 Hz,1H), 7.60 (d, J=7.4 Hz, 1H), 7.29 (m, 1H), 7.18 (d, J=11.6 Hz, 1H), 5.52(s, 2H), 4.75 (d, J=5.2 Hz, 1H), 3.51 (m, 1H), 3.32 (m, 1H), 2.01 (m,1H), 1.89 (m, 1H), 1.56-1.65 (m, 2H), 1.12-1.31 (m, 4H); LCMS (ESI) m/z398 (M+H)⁺.

Example 155 Preparation of(1R,2R)-2-((6-((6-morpholinoimidazo[1,2-b]pyridazin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

(1R,2R)-2-((6-((6-Morpholinoimidazo[1,2-b]pyridazin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(55 mg, 13%) was obtained as a yellow powder using a procedure analogousto that described in Step 6 of Example 117, substituting6-morpholinopyridazin-3-amine (Ref: U.S. Pat. No. 4,104,385 A1, 1978)and2-chloro-3-(2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)propanalfrom Step 2 of Example 153, respectively, for 2-aminoisonicotinonitrileand 2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal used inExample 117. ¹H NMR (500 MHz, DMSO-d₆) δ 7.87 (d, J=7.8 Hz, 1H), 7.81(d, J=9.9 Hz, 1H), 7.58 (s, 1H), 7.35 (s, 1H), 7.24 (d, J=8.3 Hz, 1H),7.13 (d, J=8.3 Hz, 1H), 7.09 (d, J=9.9 Hz, 1H), 4.78 (br s, 1H), 4.17(s, 2H), 3.72 (d, J=4.7 Hz, 4H), 3.50 (br s, 2H), 3.42-3.49 (m, 4H),2.04 (d, J=11.9 Hz, 1H), 1.87 (d, J=10.4 Hz, 1H), 1.53-1.71 (m, 2H),1.10-1.37 (m, 4H). LCMS (ESI) m/z 465 (M+H)⁺.

Example 156 Preparation of(1R,2R)-2-((4-chloro-6-((6-morpholinoimidazo[1,2-b]pyridazin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

(1R,2R)-2-((4-Chloro-6-((6-morpholinoimidazo[1,2-b]pyridazin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(25 mg, 6%) was obtained as a yellow powder using a procedure analogousto that described in Step 6 of Example 117, substituting6-morpholinopyridazin-3-amine (Ref: U.S. Pat. No. 4,104,385 A1, 1978)and2-chloro-3-(4-chloro-2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)propanal(minor product from Step 2 of Example 153), respectively, for2-aminoisonicotinonitrile and2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal used in Example117. ¹H NMR (500 MHz, DMSO-d₆) δ 8.20 (d, J=7.3 Hz, 1H), 7.82 (d, J=9.9Hz, 1H), 7.56 (s, 1H), 7.40 (s, 1H), 7.27 (s, 1H), 7.10 (d, J=9.9 Hz,1H), 4.83 (br s, 1H), 4.17 (s, 2H), 3.66-3.80 (m, 4H), 3.44 (d, J=4.7Hz, 4H), 2.02 (d, J=7.8 Hz, 1H), 1.88 (d, J=11.4 Hz, 1H), 1.63 (br s,2H), 1.10-1.37 (m, 4H). LCMS (ESI) m/z 499, 501 (M+H)⁺.

Example 157 Preparation of(1R,2R)-2-((6-(imidazo[2,1-b]thiazol-5-ylmethyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: A stirred mixture of2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal from Step 4 ofExample 117 (500 mg, 1.84 mmol) and thiazol-2-amine (370 mg, 3.68 mmol)in 1-butanol (22 mL) was heated at reflux overnight. The mixture wascooled to rt and water (120 mL) was added. The mixture was extractedwith EtOAc (60 mL×3). The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by silica gel chromatography elutingwith 50:1 to 20:1 DCM/MeOH to afford6-(imidazo[2,1-b]thiazol-5-ylmethyl)-2-(methylthio)benzo[d]thiazole as ayellow solid (350 mg, 60%). ¹H NMR (300 MHz, CDCl₃) δ 7.80 (d, J=8.4 Hz,1H), 7.55 (d, J=1.2 Hz, 1H), 7.29 (d, J=1.8 Hz, 1H), 7.16 (d, J=0.9 Hz,1H), 6.99 (d, J=4.5 Hz, 1H), 6.71 (dd, J=0.9 Hz, J=4.5 Hz, 1H), 4.24 (s,2H), 2.78 (s, 3H). LCMS (ESI) m/z 318 (M+H)⁺.

Step 2: To a solution of6-(imidazo[2,1-b]thiazol-5-ylmethyl)-2-(methylthio)benzo[d]thiazole (350mg, 1.1 mmol) in DCM (20 mL) was added m-CPBA (240 mg, 1.4 mmol) at 0°C. The reaction mixture was stirred for 2 hat 0° C., then aq Na₂S₂O₃ (20mL) was added and the mixture was stirred for 0.5 h. The organic layerwas separated and dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by silica gel chromatographyeluting with 50:1 to 20:1 DCM/MeOH to afford6-(imidazo[2,1-b]thiazol-5-ylmethyl)-2-(methylsulfinyl)benzo[d]thiazoleas a yellow solid (310 mg, 85%). ¹H NMR (300 MHz, CDCl₃) δ 8.00 (d,J=8.4 Hz, 1H), 7.82 (d, J=0.9 Hz, 1H), 7.43 (dd, J=1.5, 8.4 Hz, 1H),7.18 (s, 1H), 7.03 (d, J=4.5 Hz, 1H), 6.75 (dd, J=0.9, 4.5 Hz, 1H), 4.32(s, 2H), 3.07 (s, 3H). LCMS (ESI) m/z 334 (M+H)⁺.

Step 3: A mixture of 6-(imidazo[2,1-b]thiazol-5-ylmethyl)-2-(methylsulfinyl)benzo[d]thiazole (310 mg, 0.93mmol), (1R,2R)-2-aminocyclohexanol (321 mg, 2.79 mmol) and DIEA (240 mg,1.86 mmol) in NMP (10 mL) was stirred for 1 d at 130° C. The mixture wascooled to rt and water (50 mL) was added. The mixture was extracted withEtOAc (100 mL×3). The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography eluting with 50:1 to10:1 DCM/MeOH, and the product was further purified by preparative HPLCto afford(1R,2R)-2-((6-(imidazo[2,1-b]thiazol-5-ylmethyl)benzo[d]thiazol-2-yl)amino)cyclohexanolas a brown solid (100 mg, 28%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.84 (d,J=7.2 Hz, 1H), 7.68 (d, J=4.5 Hz, 1H), 7.54 (d, J=1.8 Hz, 1H), 7.27 (d,J=8.1 Hz, 1H), 7.20 (dd, J=0.9, 4.2 Hz, 1H), 7.10 (dd, J=1.8, 8.4 Hz,1H), 7.02 (s, 1H), 4.71 (d, J=4.8 Hz, 1H), 4.15 (s, 2H), 3.52-3.49 (m,1H), 3.39-3.36 (m, 1H), 2.05-2.01 (m, 1H), 1.90-1.86 (m, 1H), 1.65-1.59(m, 2H), 1.30-1.16 (m, 4H). LCMS (ESI) m/z 385 (M+H)⁺.

Example 158 Preparation of(1R,2R)-2-((6-((6-chloroimidazo[1,2-b]pyridazin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: A mixture of2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal from Step 4 ofExample 117 (1.5 g, 5.5 mmol) and 6-chloropyridazin-3-amine (1.4 g, 11mmol) in 1-butanol (60 mL) was heated at reflux overnight. Then themixture was cooled to rt and water (120 mL) was added. The mixture wasextracted with EtOAc (60 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by silica gel chromatography elutingwith 50:1 to 20:1 DCM/MeOH to afford6-((6-chloroimidazo[1,2-b]pyridazin-3-yl)methyl)-2-(methylthio)benzo[d]thiazoleas a yellow solid (1.6 g, 84%). ¹H NMR (300 MHz, CDCl₃) δ 7.89 (d, J=9.6Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.68 (dd, J=0.6, 1.2 Hz, 1H), 7.53 (s,1H), 7.37 (dd, J=1.8, 8.4 Hz, 1H), 7.03 (d, J=9.3 Hz, 1H), 4.40 (s, 2H),2.78 (s, 3H). LCMS (ESI) m/z 347 (M+H)⁺.

Step 2: To a solution of6-((6-chloroimidazo[1,2-b]pyridazin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole(1.6 g, 4.6 mmol) in DCM (90 mL) was added m-CPBA (1.0 g, 5.8 mmol) at0° C. The reaction mixture was stirred for 2 h at 0° C., then aq Na₂S₂O₃(45 mL) was added and the mixture was stirred for 0.5 h. The organiclayer was separated, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by silica gel chromatographyeluting with 50:1 to 20:1 DCM/MeOH to afford6-((6-chloroimidazo[1,2-b]pyridazin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazoleas a yellow solid (1.68 g, 100%). ¹H NMR (300 MHz, CDCl₃) δ 8.00 (d,J=8.4 Hz, 1H), 7.92 (d, J=3.6 Hz, 1H), 7.89 (s, 1H), 7.58 (s, 1H), 7.53(dd, J=2.1, 8.7 Hz, 1H), 7.05 (d, J=9.3 Hz, 1H), 4.48 (s, 2H), 3.07 (s,3H). LCMS (ESI) m/z 363 (M+H)⁺.

Step 3: A mixture of6-((6-chloroimidazo[1,2-b]pyridazin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole(1.0 g, 2.7 mmol), (1R,2R)-2-aminocyclohexanol (0.93 g, 8.1 mmol) andDIEA (697 mg, 5.4 mmol) in NMP (40 mL) was stirred for 2 d at 140° C.The mixture was cooled to rt and water (150 mL) was added. The mixturewas extracted with EtOAc (100 mL×3). The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by silica gel chromatographyeluting with 50:1 to 10:1 DCM/MeOH to afford(1R,2R)-2-((6-((6-chloroimidazo[1,2-b]pyridazin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolas a brown solid (530 mg, 46%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.20 (d,J=9.6 Hz, 1H), 7.86 (d, J=7.2 Hz, 1H), 7.63 (s, 1H), 7.54 (d, J=1.8 Hz,1H), 7.32 (d, J=9.9 Hz, 1H), 7.27 (d, J=1.8 Hz, 1H), 7.12 (dd, J=1.5,8.4 Hz, 1H), 4.73 (d, J=5.1 Hz, 1H), 4.29 (s, 2H), 3.52-3.49 (m, 1H),3.39-3.36 (m, 1H), 2.05-2.01 (m, 1H), 1.90-1.86 (m, 1H), 1.65-1.59 (m,2H), 1.30-1.16 (m, 4H). LCMS (ESI) m/z 414 (M+H)⁺.

Example 159 Preparation of(1R,2R)-2-((6-((6-(1H-pyrazol-1-yl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1:(1R,2R)-2-((6-((6-Iodoimidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(50 mg, 13%) was obtained as a light brown solid using a procedureanalogous to that described in Step 6 of Example 117, substituting5-iodopyridin-2-amine and2-chloro-3-(2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)propanalfrom Step 2 of Example 153, respectively, for 2-aminoisonicotinonitrileand 2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal used inExample 117. LCMS (ESI) m/z 505 (M+H)⁺.

Step 2:(1R,2R)-2-((6-((6-(1H-Pyrazol-1-yl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(7 mg, 16%) was obtained as a light tan solid using a procedureanalogous to that described in Example 141, substituting(1R,2R)-2-((6-((6-iodoimidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolfrom Step 1 of this Example for(1R,2R)-2-((6-((6-iodo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolused in Example 141. ¹H NMR (500 MHz, DMSO-d₆) δ 8.70 (br s, 1H), 8.48(d, J=2.1 Hz, 1H), 7.92 (d, J=7.3 Hz, 1H), 7.76 (br s, 2H), 7.73 (br s,1H), 7.54 (s, 1H), 7.28 (d, J=8.3 Hz, 1H), 7.12 (d, J=8.3 Hz, 1H), 6.57(s, 1H), 4.79 (br s, 1H), 4.36 (s, 2H), 3.49 (d, J=6.7 Hz, 2H), 2.04 (d,J=11.4 Hz, 1H), 1.87 (d, J=10.4 Hz, 1H), 1.53-1.71 (m, 2H), 1.08-1.36(m, 4H). LCMS (ESI) m/z 445 (M+H)⁺.

Example 160 Preparation of(1R,2R)-2-((6-((5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

(1R,2R)-2-((6-((5-(1H-pyrazol-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(18 mg, 20%) was obtained as a solid using a procedure analogous to thatdescribed in Example 141, substituting(1R,2R)-2-((6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolfrom Step 5 of Example 183 for(1R,2R)-2-((6-((6-iodo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolused in Example 141. ¹H NMR (500 MHz, DMSO-d₆) δ 8.43-8.53 (m, 2H), 8.06(d, J=1.6 Hz, 1H), 7.99 (d, J=7.8 Hz, 1H), 7.69-7.75 (m, 2H), 7.64-7.68(m, 2H), 7.30 (d, J=8.3 Hz, 1H), 7.22 (d, J=8.3 Hz, 1H), 6.51 (d, J=2.1Hz, 1H), 5.50 (s, 2H), 4.76 (br m, 1H), 3.48-3.56 (br m, 2H), 2.02 (m,1H), 1.87 (m, 1H), 1.52-1.68 (m, 2H), 1.09-1.35 (m, 4H); LCMS (ESI) m/z445 (M+H)⁺.

Example 161 Preparation of(1R,2R)-2-((6-((5-(1H-1,2,4-triazol-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

(1R,2R)-2-((6-((5-(1H-1,2,4-Triazol-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(10 mg, 8%) was obtained as a solid using a procedure analogous to thatdescribed in Example 141, substituting(1R,2R)-2-((6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolfrom Step 5 of Example 183 and 1H-1,2,4-triazole, respectively, for(1R,2R)-2-((6-((6-iodo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanoland 1H-pyrazole used in Example 141. ¹H NMR (500 MHz, DMSO-d₆) δ 9.23(s, 1H), 8.54 (s, 1H), 8.20 (s, 1H), 8.12 (s, 1H), 7.97 (d, J=7.3 Hz,1H), 7.71-7.74 (m, 2H), 7.68 (s, 1H), 7.30 (d, J=8.3 Hz, 1H), 7.22 (d,J=8.3 Hz, 1H), 5.52 (s, 2H), 4.74 (br s, 1H), 3.48-3.56 (br m, 2H), 2.02(m, 1H), 1.87 (br s, 1H), 1.52-1.72 (m, 2H), 1.10-1.33 (m, 4H); LCMS(ESI) m/z 446 (M+H)⁺.

Example 162 Preparation of(1S,2R)-2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: A mixture of acetic anhydride (49 mL, 0.5 mol) and formic acid(19 mL, 0.5 mol) was heated at 60° C. for 3 h.5-Fluoro-3-nitropyridin-2-amine was added and the mixture was stirred at60° C. for 1 h. The mixture was concentrated under reduced pressure andthe residue was stirred vigorously in diethyl ether (200 mL) for 30minutes. The solid was collected by filtration to affordN-(5-fluoro-3-nitropyridin-2-yl)formamide (4.5 g, 96%) as an orangesolid which did not require further purification. LCMS (ESI) m/z 186(M+H)⁺.

Step 2:N-(5-Fluoro-3-nitropyridin-2-yl)-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)formamidewas synthesized as an yellow solid (4 g, 82%) using a procedureanalogous to that described in Step 3 of Example 47, substitutingN-(5-fluoro-3-nitropyridin-2-yl)formamide from the previous step for5-bromo-6-methoxy-1H-benzo[d]imidazole used in Example 47. LCMS (ESI)m/z 379 (M+H)⁺.

Step 3: A stirred mixture ofN-(5-fluoro-3-nitropyridin-2-yl)-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)formamideand iron powder (6 g, 108 mmol) in EtOH (70 mL) and HOAc (30 mL) washeated at reflux for 2 h. The mixture was cooled to rt, filtered, andthe filtrate was concentrated under reduced pressure. The residue waspurified by silica gel flash chromatography, eluting with a gradient of100% hexanes to 100% EtOAc, to afford6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole(1 g, 28%) as a white foam. ¹H NMR (500 MHz, DMSO-d₆) δ 8.72 (s, 1H),8.40 (t, J=2.0 Hz, 1H), 8.09 (dd, J=2.6, 9.5 Hz, 1H), 7.99 (s, 1H), 7.80(d, J=8.4 Hz, 1H), 7.45 (dd, J=1.5, 8.4 Hz, 1H), 5.61 (s, 2H), 2.76 (s,3H); LCMS (ESI) m/z 331 (M+H)⁺.

Step 4: 6-((6-Fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole was synthesized as a white foam (1.8 g) usinga procedure analogous to that described in Step 6 of Example 36,substituting6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazolefrom the previous step for6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole usedin Example 36. LCMS (ESI) m/z 347 (M+H)⁺.

Step 5: To a suspension of6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole(1.0 g, 3.0 mmol) and (1S,2R)-2-aminocyclohexanol hydrochloride (916 mg,6 mmol) in anhydrous DMA (12 mL) was added DIEA (1.6 mL, 9.0 mmol). Themixture was heated in a sealed tube at 110° C. for 12 h. The mixture wascooled to rt and additional (1S,2R)-2-aminocyclohexanol hydrochloride(458 mg, 3 mmol) and DIEA (530 μL, 3 mmol) were added. The mixture wasfurther heated in a sealed tube at 120° C. for 12 h. The mixture wascooled to rt and partitioned between EtOAc (200 mL) and 0.5 M aq K₂CO₃(100 mL). The organic layer was separated, washed with brine (100 mL),dried over Na₂SO₄, filtered, and concentrated under reduced pressure.The residue was purified by silica gel flash chromatography, elutingwith 5% MeOH in CH₂Cl₂, then by reverse-phase preparative HPLC using amixture of water (5% CH₃CN, 0.05% HCOOH) and CH₃CN (0.05% HCOOH) as themobile phase and Varian Pursuit XRs C18 column as the stationary phaseto afford(1S,2R)-2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(89 mg, 7%) as a white powder. ¹H NMR (500 MHz, DMSO-d₆) δ 8.67 (s, 1H),8.41 (s, 1H), 8.06 (dd, J=2.5, 9.5 Hz, 1H), 7.85 (d, J=7.5 Hz, 1H), 7.66(s, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.21 (dd, J=1.3, 8.3 Hz, 1H), 5.47 (s,2H), 4.67 (m, 1H), 3.90 (m, 1H), 3.84 (m, 1H), 1.64-1.74 (m, 2H),1.43-1.63 (m, 4H), 1.25-1.34 (m, 2H); LCMS (ESI) m/z 398 (M+H)⁺.

Example 163 Preparation oftrans-4-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

To a stirred suspension of6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole(119 g, 0.3 mmol) from Step 4 of Example 162 andtrans-4-aminocyclohexanol (119 mg, 1.0 mmol) in anhydrous DMA (1 mL) wasadded DIEA (180 μL, 1.0 mmol). The mixture was heated in a sealed tubeat 110° C. for 15 h. The mixture was cooled to rt and was purified byreverse-phase preparative HPLC using a mixture of water (5% CH₃CN, 0.05%HCOOH) and CH₃CN (0.05% HCOOH) as the mobile phase and Varian PursuitXRs C18 column as the stationary phase to affordtrans-4-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(50 mg, 37%) as a white powder. ¹H NMR (500 MHz, DMSO-d₆) δ 8.67 (s,1H), 8.41 (s, 1H), 8.06 (dd, J=2.6, 9.3 Hz, 1H), 7.92 (d, J=7.3 Hz, 1H),7.66 (s, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 5.48 (s,2H), 4.55 (m, 1H), 3.60 (m, 1H), 3.40 (m, 1H), 1.93-2.03 (m, 2H),1.78-1.87 (m, 2H), 1.19-1.30 (m, 4H); LCMS (ESI) m/z 398 (M+H)⁺.

Example 164 Preparation of(1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-7-fluorobenzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: 6-(Methoxycarbonyl)-7-fluorobenzo[d]thiazole-2-thiolatepotassium salt was synthesized as a brown oil (1.2 g) using a procedureanalogous to that described in Step 1 of Example 114, substitutingmethyl 4-amino-2,3-difluorobenzoate for ethyl 6-amino-5-bromonicotinateused in Example 114. The material was used in the next step withoutfurther purification. LCMS (ESI) m/z 243 (M+H)⁺.

Step 2: Methyl 7-fluoro-2-(methylthio)benzo[d]thiazole-6-carboxylate wassynthesized as a clear oil (400 mg, 29%) using a procedure analogous tothat described in Step 2 of Example 114, substituting6-(methoxycarbonyl)-7-fluorobenzo[d]thiazole-2-thiolate potassium saltfrom the previous step for ethyl2-mercaptothiazolo[4,5-b]pyridine-6-carboxylate potassium salt used inExample 114. ¹H NMR (500 MHz, DMSO-d₆) δ 7.96 (m, 1H), 7.77 (d, J=8.6Hz, 1H), 3.89 (s, 3H), 2.85 (s, 3H); LCMS (ESI) m/z 258 (M+H)⁺.

Step 3: (7-Fluoro-2-(methylthio)benzo[d]thiazol-6-yl)methanol wassynthesized as a white solid (249 mg, 69%) using a procedure analogousto that described in Step 3 of Example 36, substituting methyl7-fluoro-2-(methylthio)benzo[d]thiazole-6-carboxylate from the previousstep for ethyl 2-(methylthio)benzo[d]thiazole-6-carboxylate used inExample 36. ¹H NMR (500 MHz, DMSO-d₆) δ 7.70 (d, J=8.4 Hz, 1H), 7.56 (t,J=7.8 Hz, 1H), 5.39 (t, J=5.8 Hz, 1H), 4.64 (d, J=5.7 Hz, 2H), 2.81 (s,3H); LCMS (ESI) m/z 230 (M+H)⁺.

Step 4: 6-(Chloromethyl)-7-fluoro-2-(methylthio)benzo[d]thiazole wassynthesized as a white solid (258 mg) using a procedure analogous tothat described in Step 4 of Example 114, substituting methyl(7-fluoro-2-(methylthio)benzo[d]thiazol-6-yl)methanol from the previousstep for (2-(methylthio)thiazolo[4,5-b]pyridin-6-yl)methanol used inExample 114. LCMS (ESI) m/z 248 (M+H)⁺.

Step 5:6-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)-7-fluoro-2-(methylthio)benzo[d]thiazolewas synthesized as a yellow solid (200 mg, 61%) using a procedureanalogous to that described in Step 5 of Example 114, substituting6-(chloromethyl)-7-fluoro-2-(methylthio)benzo[d]thiazole from theprevious step for 6-(chloromethyl)-2-(methylthio)thiazolo[4,5-b]pyridineused in Example 114. The regiochemistry of the alkylation was determinedby 2-dimensional nuclear Overhauser effect (NOE) experiment. ¹H NMR (500MHz, DMSO-d₆) δ 8.60 (s, 1H), 8.36 (dd, J=1.0, 4.7 Hz, 1H), 8.10 (dd,J=1.1, 8.0 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.42 (t, J=8.0 Hz, 1H), 7.29(dd, J=4.8, 8.0 Hz, 1H), 5.68 (s, 2H), 2.80 (s, 3H); LCMS (ESI) m/z 331(M+H)⁺.

Step 6:6-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)-7-fluoro-2-(methylsulfinyl)benzo[d]thiazolewas synthesized as a yellow solid (350 mg) using a procedure analogousto that described in Step 6 of Example 36, substituting6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-7-fluoro-2-(methylthio)benzo[d]thiazolefrom the previous step for6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole usedin Example 36. LCMS (ESI) m/z 347 (M+H)⁺.

Step 7:(1R,2R)-2-((6-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)-7-fluorobenzo[d]thiazol-2-yl)amino)cyclohexanolwas synthesized as a white powder (75 mg, 31%) using a procedureanalogous to that described in Step 7 of Example 36, substituting6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-7-fluoro-2-(methylsulfinyl)benzo[d]thiazolefrom the previous step for6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazoleused in Example 36. ¹H NMR (500 MHz, DMSO-d₆) δ 8.53 (s, 1H), 8.37 (dd,J=1.2, 4.7 Hz, 1H), 8.26 (d, J=7.6 Hz, 1H), 8.09 (dd, J=1.2, 8.1 Hz,1H), 7.29 (dd, J=4.8, 8.0 Hz, 1H), 7.11-7.23 (m, 2H), 5.56 (s, 2H), 4.77(d, J=4.9 Hz, 1H), 3.50 (m, 1H), 3.32 (m, 1H), 2.03 (m, 1H), 1.88 (m,1H), 1.56-1.68 (m, 2H), 1.12-1.32 (m, 4H); LCMS (ESI) m/z 398 (M+H)⁺.

Example 165 Preparation of(1R,2R)-2-((6-((6-methoxyimidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

(1R,2R)-2-((6-((6-Methoxyimidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(58 mg, 6%) was obtained as a light tan solid using a procedureanalogous to that described in Step 6 of Example 117, substituting5-methoxypyridin-2-amine and2-chloro-3-(2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)propanalfrom Step 2 of Example 153, respectively, for 2-aminoisonicotinonitrileand 2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal used inExample 117. ¹H NMR (500 MHz, DMSO-d₆) δ 7.88 (d, J=7.4 Hz, 1H), 7.78(s, 1H), 7.55 (s, 1H), 7.47 (d, J=9.8 Hz, 1H), 7.30 (s, 1H), 7.28 (d,J=8.4 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 7.00 (dd, J=2.0, 9.8 Hz, 1H),4.76 (br s, 1H), 4.26 (s, 2H), 3.74 (s, 3H), 3.51 (br s, 2H), 2.04 (d,J=12.8 Hz, 1H), 1.87-1.92 (m, 1H), 1.55-1.71 (m, 2H), 1.11-1.35 (m, 4H).LCMS (ESI) m/z 409 (M+H)⁺.

Example 166 Preparation of(1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-4-bromobenzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: To a stirred mixture of 4-amino-3-fluorobenzonitrile (5 g, 37mmol) in anhydrous CH₂Cl₂ (40 mL) under Ar at rt was added dropwiseN-bromosuccinimide (6.5 g, 37 mmol). After 15 h, the mixture wasconcentrated under reduced pressure. The residue was purified by silicagel flash chromatography eluting with a gradient of 100% hexanes to 50%EtOAc in hexanes to afford 4-amino-3-bromo-5-fluorobenzonitrile (6.4 g,81%) as a tan solid. ¹H NMR (500 MHz, DMSO-d₆) δ 7.76 (s, 1H), 7.62 (dd,J=1.5, 11.1 Hz, 1H), 6.44 (s, 2H); LCMS (ESI) m/z 214, 216 (M+H)⁺.

Step 2: 4-Bromo-6-cyanobenzo[d]thiazole-2-thiolate potassium salt wassynthesized as a brown oil (9.3 g) using a procedure analogous to thatdescribed in Step 1 of Example 154, substituting4-amino-3-bromo-5-fluorobenzonitrile from the previous step for4-amino-2,5-difluorobenzonitrile used in Example 154 and omitting thechromatography used in Step 1 of Example 154. LCMS (ESI) m/z 269, 271(M+H)⁺.

Step 3: 4-Bromo-2-(methylthio)benzo[d]thiazole-6-carbonitrile wassynthesized as a yellow solid (1.0 g, 12%) using a procedure analogousto that described in Step 2 of Example 114, substituting4-bromo-6-cyanobenzo[d]thiazole-2-thiolate potassium salt from theprevious step for ethyl 2-mercaptothiazolo[4,5-b]pyridine-6-carboxylatepotassium salt used in Example 114. LCMS (ESI) m/z 284, 286 (M+H)⁺.

Step 4: (4-Bromo-2-(methylthio)benzo[d]thiazol-6-yl)methanamine wassynthesized as a clear oil (794 mg, 79%) using a procedure analogous tothat described in Step 3 of Example 154, substituting4-bromo-2-(methylthio)benzo[d]thiazole-6-carbonitrile from the previousstep for 5-fluoro-2-(methylthio)benzo[d]thiazole-6-carbonitrile used inExample 154. LCMS (ESI) m/z 288, 290 (M+H)⁺.

Step 5:N-((4-Bromo-2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3-nitropyridin-2-aminewas synthesized as a yellow solid (115 mg, 39%) using a procedureanalogous to that described in Step 4 of Example 154, substituting(4-bromo-2-(methylthio)benzo[d]thiazol-6-yl)methanamine from theprevious step for(5-fluoro-2-(methylthio)benzo[d]thiazol-6-yl)methanamine used in Example154. LCMS (ESI) m/z 410, 412(M+H)⁺.

Step 6:N²-((4-Bromo-2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyridine-2,3-diaminewas synthesized as a red solid (120 mg) using a procedure analogous tothat described in Step 2 of Example 41, substitutingN-((4-bromo-2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3-nitropyridin-2-aminefrom the previous step for4-bromo-5-methoxy-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroanilineused in Example 41. LCMS (ESI) m/z 380, 382 (M+H)⁺.

Step 7:6-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)-4-bromo-2-(methylthio)benzo[d]thiazolewas synthesized as an orange solid (180 mg) using a procedure analogousto that described in Step 3 of Example 41, substitutingN²-((4-bromo-2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyridine-2,3-diaminefrom the previous step for4-bromo-5-methoxy-N¹-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamineused in Example 41. LCMS (ESI) m/z 390, 392 (M+H)⁺.

Step 8:6-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)-4-bromo-2-(methylsulfinyl)benzo[d]thiazolewas synthesized as a yellow foam (211 mg) using a procedure analogous tothat described in Step 6 of Example 36, substituting6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-4-bromo-2-(methylthio)benzo[d]thiazolefrom the previous step for6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole usedin Example 36. LCMS (ESI) m/z 406, 408 (M+H)⁺.

Step 9:(1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-4-bromobenzo[d]thiazol-2-yl)amino)cyclohexanolwas synthesized as a white powder (9 mg, 7%) using a procedure analogousto that described in Step 7 of Example 36, substituting6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-4-bromo-2-(methylsulfinyl)benzo[d]thiazolefrom the previous step for6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazoleused in Example 36. ¹H NMR (500 MHz, DMSO-d₆) δ 8.61 (s, 1H), 8.29-8.41(m, 2H), 8.09 (dd, J=1.2, 8.1 Hz, 1H), 7.68 (s, 1H), 7.49 (d, J=1.2 Hz,1H), 7.30 (m, 1H), 5.47 (s, 2H), 4.85 (m, 1H), 3.35 (m, 1H), 1.99 (m,1H), 1.88 (m, 1H), 1.60-1.66 (m, 2H), 1.13-1.33 (m, 5H); LCMS (ESI) m/z457, 459 (M+H)⁺.

Example 167 Preparation of(1R,2R)-2-((6-((7-(1H-pyrazol-1-yl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1:(1R,2R)-2-((6-((7-Iodoimidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(50 mg, 13%) was obtained as a light brown solid using a procedureanalogous to that described in Step 6 of Example 117, substituting4-iodopyridin-2-amine and2-chloro-3-(2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)propanalfrom Step 2 of Example 153, respectively, for 2-aminoisonicotinonitrileand 2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal used inExample 117. LCMS (ESI) m/z 505 (M+H)⁺.

Step 2:(1R,2R)-2-((6-((7-(1H-Pyrazol-1-yl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(7 mg, 16%) was obtained as a light tan solid using a procedureanalogous to that described in Example 141, substituting(1R,2R)-2-((6-((7-iodoimidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolfrom Step 1 of this Example for(1R,2R)-2-((6-((6-iodo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolused in Example 141. ¹H NMR (500 MHz, DMSO-d₆) δ 8.64 (d, J=2.6 Hz, 1H),8.32 (d, J=6.7 Hz, 1H), 7.98 (br s, 1H), 7.87 (d, J=7.3 Hz, 1H), 7.79(s, 1H), 7.54 (s, 2H), 7.44 (br s, 1H), 7.28 (d, J=8.3 Hz, 1H), 7.12 (d,J=7.3 Hz, 1H), 6.59 (s, 1H), 4.74 (br s, 1H), 4.31 (s, 2H), 3.48-3.57(m, 2H), 2.03 (d, J=10.9 Hz, 1H), 1.87 (d, J=10.4 Hz, 1H), 1.54-1.71 (m,2H), 1.09-1.38 (m, 4H). LCMS (ESI) m/z 445 (M+H)⁺.

Example 168 Preparation of(1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-4,7-difluorobenzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: 4-Amino-3-bromo-2,5-difluorobenzonitrile was synthesized as ayellow solid (2.4 g, 73%) using a procedure analogous to that describedin Step 1 of Example 166, substituting 4-amino-2,5-difluorobenzonitrilefor 4-amino-3-fluorobenzonitrile used in Example 166. ¹H NMR (500 MHz,DMSO-d₆) δ 7.71 (dd, J=5.9, 11.1 Hz, 1H), 6.89 (br s, 2H); LCMS (ESI)m/z 232, 234 (M+H)⁺.

Step 2: 6-Cyano-4,7-difluorobenzo[d]thiazole-2-thiolate potassium saltwas synthesized as a brown oil (3.93 g) using a procedure analogous tothat described in Step 1 of Example 154, substituting4-amino-3-bromo-2,5-difluorobenzonitrile from the previous step for4-amino-2,5-difluorobenzonitrile used in Example 154. LCMS (ESI) m/z 228(M+H)⁺.

Step 3: 4,7-Difluoro-2-(methylthio)benzo[d]thiazole-6-carbonitrile wassynthesized as a yellow solid (1.0 g, 37%) using a procedure analogousto that described in Step 2 of Example 114, substituting6-cyano-4,7-difluorobenzo[d]thiazole-2-thiolate potassium salt from theprevious step for ethyl 2-mercaptothiazolo[4,5-b]pyridine-6-carboxylatepotassium salt used in Example 114. ¹H NMR (500 MHz, DMSO-d₆) δ 8.04 (m,1H), 2.88 (s, 3H); LCMS (ESI) m/z 243 (M+H)⁺.

Step 4: (4,7-Difluoro-2-(methylthio)benzo[d]thiazol-6-yl)methanamine wassynthesized as a clear oil (646 mg, 64%) using a procedure analogous tothat described in Step 3 of Example 154, substituting4,7-difluoro-2-(methylthio)benzo[d]thiazole-6-carbonitrile from theprevious step for 5-fluoro-2-(methylthio)benzo[d]thiazole-6-carbonitrileused in Example 154. LCMS (ESI) m/z 247 (M+H)⁺.

Step 5:N-((4,7-Difluoro-2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3-nitropyridin-2-aminewas synthesized as a yellow oil (187 mg, 39%) using a procedureanalogous to that described in Step 4 of Example 154, substituting(4,7-difluoro-2-(methylthio)benzo[d]thiazol-6-yl)methanamine from theprevious step for(5-fluoro-2-(methylthio)benzo[d]thiazol-6-yl)methanamine used in Example154. ¹H NMR (500 MHz, CDCl₃) δ 8.99 (t, J=6.0 Hz, 1H), 8.40-8.48 (m,2H), 7.36 (dd, J=5.5, 11.0 Hz, 1H), 6.80 (dd, J=4.4, 8.4 Hz, 1H), 4.91(d, J=6.2 Hz, 2H), 2.82 (s, 3H); LCMS (ESI) m/z 369 (M+H)⁺.

Step 6:N²-((4,7-Difluoro-2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyridine-2,3-diaminewas synthesized as a yellow solid (190 mg) using a procedure analogousto that described in Step 2 of Example 41, substitutingN-((4,7-difluoro-2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3-nitropyridin-2-aminefrom the previous step for4-bromo-5-methoxy-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroanilineused in Example 41. LCMS (ESI) m/z 339 (M+H)⁺.

Step 7:6-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)-4,7-difluoro-2-(methylthio)benzo[d]thiazolewas synthesized as a orange solid (220 mg) using a procedure analogousto that described in Step 3 of Example 41, substitutingN²-((4,7-difluoro-2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyridine-2,3-diaminefrom the previous step for4-bromo-5-methoxy-N¹-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamineused in Example 41. LCMS (ESI) m/z 349 (M+H)⁺.

Step 8:6-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)-4,7-difluoro-2-(methylsulfinyl)benzo[d]thiazolewas synthesized as a yellow foam (200 mg) using a procedure analogous tothat described in Step 6 of Example 36, substituting6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-4,7-difluoro-2-(methylthio)benzo[d]thiazolefrom the previous step for6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole usedin Example 36. LCMS (ESI) m/z 364 (M+H)⁺.

Step 9:(1R,2R)-2-((6-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)-4,7-difluorobenzo[d]thiazol-2-yl)amino)cyclohexanolwas synthesized as a white powder (58 mg, 25%) using a procedureanalogous to that described in Step 7 of Example 36, substituting6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-4,7-difluoro-2-(methylsulfinyl)benzo[d]thiazolefrom the previous step for6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazoleused in Example 36. ¹H NMR (500 MHz, DMSO-d₆) δ 8.45-8.58 (m, 2H), 8.38(d, J=4.7 Hz, 1H), 8.09 (d, J=8.0 Hz, 1H), 7.29 (dd, J=4.7, 8.0 Hz, 1H),7.16 (dd, J=5.8, 10.8 Hz, 1H), 5.54 (s, 2H), 4.80 (d, J=5.2 Hz, 1H),3.51 (m, 1H), 3.35 (m, 1H), 2.02 (m, 1H), 1.88 (m, 1H), 1.57-1.67 (m,2H), 1.17-1.32 (m, 4H). LCMS (ESI) m/z 416 (M+H)⁺.

Example 169 Preparation of(1R,2R)-2-((6-((7-(1H-1,2,4-triazol-1-yl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

(1R,2R)-2-((6-((7-(1H-1,2,4-triazol-1-yl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(50 mg, 57%) was obtained as a light yellow powder using a procedureanalogous to that described in Example 141, substituting(1R,2R)-2-((6-((7-iodoimidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolfrom Step 1 of Example 167 and 1H-1,2,4-triazole, respectively, for(1R,2R)-2-((6-((6-iodo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanoland pyrazole used in Example 141. ¹H NMR (500 MHz, DMSO-d₆) δ 9.41 (s,1H), 8.40 (d, J=7.3 Hz, 1H), 8.28 (s, 1H), 8.08 (s, 1H), 7.90 (d, J=7.3Hz, 1H), 7.54 (s, 1H), 7.50 (s, 1H), 7.48 (d, J=5.7 Hz, 1H), 7.28 (d,J=8.3 Hz, 1H), 7.11 (d, J=8.3 Hz, 1H), 4.76 (br s, 1H), 4.34 (s, 2H),3.48-3.56 (m, 2H), 2.04 (d, J=11.4 Hz, 1H), 1.88-1.93 (m, 1H), 1.53-1.70(m, 2H), 1.08-1.36 (m, 4H). LCMS (ESI) m/z 446 (M+H)⁺.

Example 170 Preparation of1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]oxazol-6-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

Step 1: To a solution of 4-bromo-2-nitroaniline (400 mg, 1.84 mmol) andTFA (1.89 mL) in DCM (8 mL) at −5° C. was added NaBH(OAc)₃ (1.17 g, 5.52mmol). Then to the mixture at 0° C. was added a solution of2-(methylthio)benzo[d]oxazole-6-carbaldehyde (391 mg, 2.03 mmol) in DCM(7 mL), and the mixture was stirred at 0° C. for 2 h. The mixture wasdiluted with DCM and washed with H₂O, aq NaHCO₃ and brine. The organiclayer was dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by silica gel chromatography elutingwith 20:1 to 10:1 petroleum ether/ethyl acetate to give4-bromo-N-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)-2-nitroaniline asa yellow solid (704 mg, 97.4%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.80 (t,1H), 8.15 (s, 1H), 7.64 (s, 1H), 7.50-7.60 (m, 2H), 7.35 (d, J=8.4 Hz,1H), 6.90 (d, J=9.3 Hz, 1H), 4.72 (d, J=6.6 Hz, 1H), 2.73 (s, 3H). LCMS(ESI) m/z 394 (M+H)⁺.

Step 2: To a stirred solution of4-bromo-N-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)-2-nitroaniline(704 mg, 1.79 mmol), HOAc (2.1 mL) and methnol (2.1 mL) in DCM (18 mL)at 0° C. was added zinc dust (1.16 g, 17.9 mmol) portionwise. Afterstirring for 2 h, the mixture was filtered. The filtrate was washed withaq NaHCO₃ and brine. The organic layer was dried over NaSO₄, filteredand concentrated under reduced pressure to give4-bromo-N¹-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)benzene-1,2-diamine(469 mg, 71.9%) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.72-7.60(m, 2H), 7.53 (d, J=5.4 Hz, 1H), 6.68 (s, 1H), 6.49 (d, J=1.8 Hz, 1H),6.23 (d, J=8.1 Hz, 1H), 5.36 (t, 1H), 4.90 (s, 2H), 4.38 (d, J=6.0 Hz,2H), 2.74 (s, 3H). LCMS (ESI) m/z 365 (M+H)⁺.

Step 3: A mixture of4-bromo-N¹-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)benzene-1,2-diamine(465 mg, 2.40 mmol), triethyl orthoformate (3.8 mL), and HCOOH (0.06 mL)was stirred at 90° C. for 40 min. The reaction mixture was concentratedunder reduced pressure. The residue was purified by silica gelchromatography eluting with 1:1 petroleum ether/ethyl acetate to give6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]oxazoleas a light brown solid (327 mg, 68.3%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.50(s, 1H), 7.85 (s, 1H), 7.68 (s, 1H), 7.55-7.60 (m, 2H), 7.30-7.37 (m,2H), 5.60 (s, 2H), 2.73 (s, 3H). LCMS (ESI) m/z 375 (M+H)⁺.

Step 4: A solution of6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]oxazole(327 mg, 0.87 mmol) and m-CPBA (226 mg, 1.31 mmol) in DCM (6 mL) wasstirred at 0° C. for 3.5 h. The mixture was washed with aq Na₂S₂O₃ andbrine. The organic layer was dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography eluting with 1:5 petroleum ether/ethyl acetate togive6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole(256 mg, 75.52%) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.54 (s,1H), 7.97 (s, 1H), 7.87-7.89 (m, 2H), 7.57 (d, J=9.0 Hz, 1H), 7.46 (d,J=9.6 Hz, 1H), 7.36 (d, J=6.6 Hz, 1H), 5.68 (s, 2H), 3.18 (s, 3H). LCMS(ESI) m/z 391 (M+H)⁺.

Step 5: A mixture of6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole (206 mg, 0.53 mmol),(1R,2R)-2-aminocyclohexanol (91 mg, 0.79 mmol) and DIEA (136 mg, 1.06mmol) in DMA (4 mL) was stirred at 120° C. for 2 h. The reaction mixturewas cooled to rt, poured into water (30 mL) and extracted with ethylacetate (30 mL×3). The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by preparative HPLC to give(1R,2R)-2-((6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanolas a light yellow solid (175 mg, 74.8%). ¹H NMR (300 MHz, DMSO-d₆) δ8.46 (s, 1H), 7.81-7.84 (m, 2H), 7.56 (d, J=8.7 Hz, 1H), 7.33-7.36 (s,1H), 7.12 (s, 2H), 5.48 (s, 1H), 4.68 (d, J=4.2 Hz, 1H), 3.35 (br s,2H), 1.90 (br s, 2H), 1.62 (br s, 2H), 1.22 (br s, 4H). LCMS (ESI) m/z442 (M+H)⁺.

Step 6: A mixture of(1R,2R)-2-((6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol(126 mg, 0.29 mmol), Zn(CN)₂ (134 mg, 1.14 mmol), Pd₂(dba)₃ (53 mg, 0.06mmol) and dppf (63 mg, 0.12 mmol) in DMF (4 mL) was stirred at 130° C.for 6 h. The reaction mixture was cooled to rt, poured into water (20mL) and extracted with ethyl acetate (20 mL×2). The combined organiclayers were washed with water and brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified bypreparative HPLC to give1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]oxazol-6-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrileas a white solid (40 mg, 35.7%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.67 (s,1H), 8.20 (s, 1H), 7.83-7.78 (m, 2H), 7.61 (d, J=6.9 Hz, 1H), 7.41 (s,1H), 7.14 (s, 1H), 5.54 (s, 2H), 4.68 (d, 1H), 3.32 (br s, 2H), 1.91 (brs, 2H), 1.62 (br s, 2H), 1.22 (br s, 4H). LCMS (ESI) m/z 388 (M+H)⁺.

Example 171 Preparation of(1R,2R)-2-((6-((5-(2-morpholinoethoxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: To a mixture of1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-ol(2.4 g, 6.07 mmol) from Example 147 and 2,2-dimethoxypropane (8 g, 76.81mmol) in 1,4-dioxane (200 mL) was added para-toluenesulfonic acid (0.15g, 0.8 mmol). The reaction mixture was heated at 100° C. for 15 h. Themixture was partitioned between saturated aq NaHCO₃ and DCM. The organiclayer was separated, dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by silica gel flashchromatography eluting with 2 to 10% MeOH in DCM to afford1-((2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-ol (0.9 g,34%) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.24(s, 1H), 7.79 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.24-7.30 (m, 2H), 6.94(s, 1H), 6.68 (m, 1H), 5.43 (s, 2H), 3.68 (m, 1H), 3.05 (m, 1H), 2.67(m, 1H), 2.04 (m, 1H), 1.76-1.78 (m, 2H), 1.70 (s, 3H), 1.53 (s, 3H),1.26-1.39 (m, 4H); LCMS (ESI) m/z 435 (M+H)⁺.

Step 2: A stirred mixture of 4-(2-chloroethyl)morpholine (1 g, 5.4 mmol)and KI (4.5 g 26.8 mmol) in acetone (15 mL) was heated at 75° C. for 24h. The mixture was diluted with saturated aq NaHCO₃ and extracted withDCM. The organic layer was separated, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to afford 4-(2-iodoethyl)morpholine(0.8 g, 62%) as a pale yellow oil which was not purified further. ¹H NMR(300 MHz, CDCl₃) δ 03.71 (t, J=9.0 Hz, 4H), 3.20 (t, J=7.8 Hz, 2H), 2.72(t, J=7.8 Hz, 2H), 2.49 (t, J=9.3 Hz, 4H). LCMS (ESI) m/z 242 (M+H)⁺.

Step 3: A mixture of1-((2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-ol (100 mg,0.23 mmol) from Step 1 of this Example, 4-(2-iodoethyl)morpholine (111mg, 0.46 mmol) from Step 2 of this Example, Cs₂CO₃ (250 mg, 0.69 mmol),and NMP (2 mL) was stirred at rt for 3 h. The mixture was diluted withEtOAc and washed with brine. The organic layer was separated, dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by silica gel flash chromatography, eluting with a gradientof 33% DCM in THF to 100% THF, to afford(3aR,7aR)-2,2-dimethyl-3-(6-((5-(2-morpholinoethoxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)octahydrobenzo[d]oxazole(84 mg, 67%) as a yellow solid. ¹H NMR (300 MHz, CDCl₃) δ □7.90 (s, 1H),7.58 (d, J=8.1 Hz, 1H), 7.40 (s, 1H), 7.29 (s, 1H), 7.14-7.19 (m, 2H),6.90 (m, 1H), 5.35 (s, 2H), 4.11-4.17 (m, 2H), 3.70-3.75 (m, 4H), 3.65(m, 1H), 3.08 (m, 1H), 2.76-2.84 (m, 3H), 2.57-2.60 (m, 4H), 2.17 (m,1H), 1.82-1.92 (m, 2H), 1.78 (s, 3H), 1.46 (s, 3H), 1.33-1.39 (m, 4H);LCMS (ESI) m/z 548 (M+H)⁺.

Step 4: To a stirred mixture of(3aR,7aR)-2,2-dimethyl-3-(6-((5-(2-morpholinoethoxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)octahydrobenzo[d]oxazole(85 mg, 0.15 mmol) from the previous step in DCM (10 mL) at 0° C. wasadded methanolic HCl (3 drops). The reaction mixture was stirred at 0°C. for 10 min. The mixture was adjusted to pH˜7 by addition oftriethylamine and then concentrated under reduced pressure. The residuewas purified directly by reverse-phase preparative HPLC to afford(1R,2R)-2-((6-((5-(2-morpholinoethoxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(20 mg, 25%) as a light yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ □8.30(s, 1H), 7.97 (m, 1H), 7.62 (s, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.29 (d,J=8.1 Hz, 1H), 7.17 (d, J=6.9 Hz, 2H), 6.83 (m, 1H), 5.41 (s, 2H), 4.73(d, J=5.4 Hz, 1H), 4.08 (t, J=11.7 Hz, 2H), 3.57 (t, J=9.1 Hz, 4H),3.47-3.52 (m, 2H), 2.68 (t, J=11.7 Hz, 2H), 2.46 (t, J=9.3 Hz, 4H), 2.02(m, 1H), 1.87 (m, 1H), 1.59-1.63 (br s, 2H), 1.16-1.28 (m, 4H). LCMS(ESI) m/z 508 (M+H)⁺.

Example 172 Preparation of(1R,2R)-2-((6-((5-(2-hydroxyethoxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: A stirred mixture of1-((2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-ol (60 mg,0.14 mmol) from Step 1 of Example 171, 2-iodoethanol (60 mg, 0.35 mmol),Cs₂CO₃ (137 mg, 0.42 mmol), and NMP (2 mL) was heated at 100° C. for 24h. The mixture was diluted with EtOAc and washed with brine. The organiclayer was separated, dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by preparative TLC to afford2-((1-((2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)oxy)ethanol(26 mg, 39%) as a light yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 7.93 (s,1H), 7.58 (d, J=8.1 Hz, 1H), 7.40 (s, 1H), 7.32 (s, 1H), 7.16-7.19 (m,2H), 6.91 (m, 1H), 5.36 (s, 2H), 4.13 (t, J=9.0 Hz, 2H), 3.98 (t, J=9.0Hz, 2H), 3.65 (m, 1H), 3.08 (m, 1H), 2.80 (m, 1H), 2.14 (m, 1H),1.84-1.92 (m, 2H), 1.78 (s, 3H), 1.63 (s, 3H), 1.28-1.40 (m, 4H); LCMS(ESI) m/z 479 (M+H)⁺.

Step 2: To a stirred mixture of2-((1-((2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)oxy)ethanol(70 mg, 0.15 mmol) from the previous step in DCM (5 mL) at 0° C. wasadded methanolic HCl (3 drops). The reaction mixture was stirred at 0°C. for 10 min. The mixture was adjusted to pH˜7 by the addition oftriethylamine and concentrated under reduced pressure. The residue waspurified directly by reverse-phase preparative HPLC to afford((1R,2R)-2-((6-((5-(2-hydroxyethoxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(30 mg, 47%) as a light yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.30(s, 1H), 7.95 (d, J=7.2 Hz, 1H), 7.62 (s, 1H), 7.40 (d, J=9.0 Hz, 1H),7.29 (d, J=8.1 Hz, 1H), 7.16-7.18 (m, 2H), 6.84 (m, 1H), 5.41 (s, 2H),4.83 (br s, 1H), 4.72 (d, J=4.5 Hz, 1H), 3.98 (t, J=9.6 Hz, 2H), 3.71(d, J=4.5 Hz, 2H), 3.52 (m, 1H), 3.33 (br s, 1H), 2.03 (m, 1H), 1.87 (m,1H), 1.61-1.63 (m, 2H), 1.22-1.28 (m, 4H); LCMS (ESI) m/z 439 (M+H)⁺.

Example 1731-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-N-methyl-1H-benzo[d]imidazole-5-carboxamide

Step 1: Methyl4-(((2-(methylthio)benzo[d]thiazol-6-yl)methyl)amino)-3-nitrobenzoate(1.80 g, 91%) was obtained as a yellow solid using a procedure analogousto that described in Step 1 of Example 127, substituting methyl4-amino-3-nitrobenzoate for 4-methyl-2-nitroaniline used in Example 127.¹H NMR (300 MHz, CDCl₃) δ 9.15 (br s, 1H), 8.63 (s, 1H), 7.98 (s, 1H),7.88 (dd, J=9.0, 2.4 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.47 (dd, J=8.7,1.8 Hz, 1H), 7.02 (d, J=9.0 Hz, 1H), 4.81 (d, J=5.7 Hz, 2H), 3.80 (s,3H), 2.77 (s, 3H); LCMS (ESI) m/z 391 (M+H)⁺.

Step 2: Methyl3-amino-4-(((2-(methylthio)benzo[d]thiazol-6-yl)methyl)amino)benzoate(1.01 g, 62%) was obtained as a yellow solid using a procedure analogousto that described in Step 2 of Example 129, substituting4-(((2-(methylthio)benzo[d]thiazol-6-yl)methyl)amino)-3-nitrobenzoatefrom Step 1 of this Example for4-fluoro-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroanilineused in Example 129. LCMS (ESI) m/z 360 (M+H)⁺.

Step 3: Methyl 1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-1Hbenzo[d]imidazole-5-carboxylate (0.42 g, 42%) was obtained as a yellowsolid using a procedure analogous to that described in Step 3 of Example130, substituting methyl3-amino-4-(((2-(methylthio)benzo[d]thiazol-6-yl)methyl)amino)benzoatefrom Step 2 of this Example forN¹-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-4-(trifluoromethyl)benzene-1,2-diamineused in Example 130. ¹H NMR (300 MHz, CDCl₃) δ 8.55 (s, 1H), 8.05 (s,1H), 7.98 (dd, J=8.7, 1.5 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.51 (s, 1H),7.26-7.32 (m, 2H), 5.48 (s, 2H), 3.94 (s, 3H), 2.77 (s, 3H); LCMS (ESI)m/z 370 (M+H)⁺.

Step 4: Methyl1-((2-(methylsulfinyl)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazole-5-carboxylate(0.40 g, 93%) was obtained as a yellow solid using a procedure analogousto that described in Step 4 of Example 130, substituting methyl1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-1Hbenzo[d]imidazole-5-carboxylate from Step 3 of this Example for2-(methylthio)-6-((5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazoleused in Example 130. ¹H NMR (300 MHz, CDCl₃) δ 8.56 (s, 1H), 8.09 (s,1H), 7.91-8.05 (m, 2H), 7.79 (s, 1H), 7.39 (dd, J=8.7, 1.6 Hz, 1H), 7.29(d, J=8.7 Hz, 1H), 5.56 (s, 2H), 3.94 (s, 3H), 3.06 (s, 3H); LCMS (ESI)m/z 386 (M+H)⁺.

Step 5: Methyl1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)ethyl)-1H-benzo[d]imidazole-5-carboxylate(0.27 g, 60%) was obtained as a white solid using a procedure analogousto that described in Step 5 of Example 130, substituting methyl1-((2-(methylsulfinyl)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazole-5-carboxylatefrom Step 4 of this Example for 2-(methylsulfinyl)-6-((5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazoleused in Example 130. ¹H NMR (300 MHz, CDCl₃) δ 8.51 (s, 1H), 8.01 (s,1H), 9.76 (dd, J=8.4, 1.5 Hz, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.30 (d,J=8.4 Hz, 1H), 7.13 (dd, J=8.1, 1.2 Hz, 1H), 7.27 (s, 1H), 5.35 (s, 2H),3.92 (s, 3H), 3.48-3.51 (m, 2H), 2.01-2.03 (m, 2H), 1.70 (br m, 2H),1.25-1.32 (m, 4H); LCMS (ESI) m/z 438 (M+H)⁺.

Step 6: A mixture of methyl1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)ethyl)-1H-benzo[d]imidazole-5-carboxylate(0.27 g, 0.61 mmol) from the previous step, lithium hydroxide (84 mg,3.05 mmol), THF (20 mL) and water (4 mL) was stirred at rt for 3 h. Themixture was concentrated under reduced pressure and the pH was adjustedto 4-5. The mixture was extracted with EtOAc (30 mL×3) and the combinedorganic layers were washed with water (10 mL×2), dried over Na₂SO₄,filtered, and concentrated under reduced pressure to afford1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazole-5-carboxylicacid (0.15 g, 58%) as a white solid which was not purified further. ¹HNMR (300 MHz, CDCl₃) δ 8.25 (s, 1H), 7.94 (s, 1H), 7.81 (d, J=8.4 Hz,1H), 7.27 (m, 1H), 7.18-7.21 (m, 2H), 7.06 (m, 1H), 5.25 (s, 2H),3.30-3.39 (m, 2H), 1.98 (m, 1H), 1.86 (m, 1H), 1.53-1.56 (m, 2H),1.06-1.16 (m, 4H); LCMS (ESI) m/z 424 (M+H)⁺.

Step 7: A mixture of1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazole-5-carboxylicacid (100 mg, 0.24 mmol) from the previous step, methylamine (1 mL, 22.5mmol), DIEA (91 mg, 0.35 mmol) and DMF (5 mL) was stirred at rt for 15min. HATU (180 mg, 0.23 mmol) was added and the mixture was stirred atrt for 15 h. The reaction mixture was diluted with EtOAc (50 mL) andwashed sequentially with water (10 mL) and brine (10 mL). The organiclayer was separated, dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified directly by reverse-phasepreparative HPLC to afford1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-N-methyl-1H-benzo[d]imidazole-5-carboxamide(26 mg, 25%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.49 (s, 1H),8.37 (br s, 1H), 8.16 (s, 1H), 7.95 (d, J=7.5 Hz, 1H), 7.58-7.75 (m,3H), 7.29 (m, 1H), 7.20 (m, 1H), 5.49 (s, 2H), 4.72 (d, J=5.1 Hz, 1H),3.50 (m, 1H), 3.35 (m, 1H), 2.50 (s, 3H), 2.04 (m, 1H), 1.88 (m, 1H),1.60-1.62 (m, 2H), 1.18-1.21 (m, 4H). LCMS (ESI) m/z 436 (M+H)⁺.

Example 174 Preparation of(1R,2R)-2-((6-((5-(3,6-dihydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

A stirred mixture of(1R,2R)-2-((6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(300 mg, 0.59 mmol) from Step 5 of Example 183,2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(188 mg, 0.89 mmol), Na₂CO₃ (126 mg, 1.19 mmol), 1,4-dioxane (3 mL) andwater (0.5 mL) was purged with a stream of nitrogen for 10 min.[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (44 mg,0.59 mmol) was added and the mixture was heated at 100° C. for 2 h. Thereaction mixture was cooled to rt and partitioned between EtOAc andwater. The organic layer was separated, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by silicagel flash chromatography eluting with 30:1 DCM: MeOH and then byreverse-phase preparative HPLC to afford (1R,2R)-2-((6-((5-(3,6-dihydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (54 mg, 20%) as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 8.38 (s, 1H), 7.94 (d, J=7.8 Hz, 1H), 7.67 (d, J=1.5 Hz,1H), 7.63 (d, J=1.8 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.35 (m, 1H), 7.29(d, J=8.1 Hz, 1H), 7.18 (m, 1H), 6.19 (s, 1H), 5.46 (s, 2H), 4.71 (d,J=5.1 Hz, 1H), 4.22 (d, J=2.7 Hz, 2H), 3.81-3.84 (m, 2H), 3.51 (m, 1H),3.38 (m, 1H), 2.02 (m, 1H), 2.00 (m, 1H), 1.61 (br s, 2H), 1.14-1.29 (m,4H); LCMS (ESI) m/z 460 (M+H)⁺.

Example 175 Preparation of(1R,2R)-2-((6-((5-(3,3,3-trifluoroprop-1-en-2-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

(1R,2R)-2-((6-((5-(3,3,3-Trifluoroprop-1-en-2-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(71 mg, 25%) was obtained as a white solid using a procedure analogousto that described in Example 174, substituting4,4,5,5-tetramethyl-2-(3,3,3-trifluoroprop-1-en-2-yl)-1,3,2-dioxaborolanefor2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneused in Example 174. ¹H NMR (300 MHz, DMSO-d₆) δ 8.49 (s, 1H), 7.95 (d,J=7.8 Hz, 1H), 7.75 (s, 1H), 7.67 (d, J=1.2 Hz, 1H), 7.63 (d, J=8.4 Hz,1H), 7.35 (d, J=8.4 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.20 (m, 1H), 6.04(t, J=1.8 Hz, 2H), 5.49 (s, 2H), 4.17 (d, J=5.1 Hz, 1H), 3.51 (m, 1H),3.35 (m, 1H), 2.03 (m, 1H), 1.88 (m, 1H), 1.60-1.64 (m, 2H), 1.18-1.25(m, 4H); LCMS (ESI) m/z 473 (M+H)⁺.

Example 176 Preparation of(R)—N-(cyclohex-2-en-1-yl)-6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-amine

To a stirred mixture of(1R,2R)-2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(156 mg, 0.4 mmol) from Example 162 in CH₂Cl₂ (10 mL) at −78° C. underargon was added diethylaminosulfur trifluoride (63 μL, 0.5 mmol). Afterstirring the mixture for 3 h, additional diethylaminosulfur trifluoride(63 μL, 0.5 mmol) was added. After the mixture was stirred for a further3 h, it was poured over ice. Additional CH₂Cl₂ (50 mL) was added and themixture was stirred until the ice was melted. The layers were separatedand the organic layer was washed with brine (50 mL), dried over MgSO₄,filtered, and concentrated under reduced pressure. The residue waspurified by reverse-phase preparative HPLC using a mixture of water (5%CH₃CN, 0.05% HCOOH) and CH₃CN (0.05% HCOOH) as the mobile phase andVarian Pursuit XRs C18 column as the stationary phase to afford(R)—N-(cyclohex-2-en-1-yl)-6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-amine(5 mg, 3%) as a white powder. ¹H NMR (500 MHz, DMSO-d₆) δ 8.67 (s, 1H),8.41 (s, 1H), 8.03-8.13 (m, 2H), 7.68 (s, 1H), 7.32 (d, J=8.3 Hz, 1H),7.24 (dd, J=1.3, 8.3 Hz, 1H), 5.83 (m, 1H), 5.72 (m, 1H), 5.48 (s, 2H),4.40 (br s, 1H), 1.95-2.03 (m, 2H), 1.90 (m, 1H), 1.70 (m, 1H),1.54-1.62 (m, 2H); LCMS (ESI) m/z 380 (M+H)⁺.

Example 177 Preparation of(1R,2R)-2-((6-((6-bromoimidazo[1,2-b]pyridazin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

(1R,2R)-2-((6-((6-Bromoimidazo[1,2-b]pyridazin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(25 mg, 28%) was obtained as a light tan solid using a procedureanalogous to that described in Step 6 of Example 117, substituting6-bromopyridazin-3-amine and2-chloro-3-(2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)propanalfrom Step 2 of Example 153, respectively, for 2-aminoisonicotinonitrileand 2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal used inExample 117. ¹H NMR (500 MHz, DMSO-d₆) δ 8.09 (d, J=9.8 Hz, 1H), 7.89(d, J=7.4 Hz, 1H), 7.59 (s, 1H), 7.54 (s, 1H), 7.39 (d, J=9.4 Hz, 1H),7.27 (d, J=7.9 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 4.76 (br s, 1H), 4.29(s, 2H), 3.47-3.59 (m, 2H), 2.04 (d, J=11.8 Hz, 1H), 1.86-1.92 (m, 1H),1.55-1.69 (m, 2H), 1.11-1.34 (m, 4H). LCMS (ESI) m/z 458, 460 (M+H)⁺.

Example 178 Preparation of(1R,2R)-2-((6-((6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

(1R,2R)-2-((6-((6-(4-Methylpiperazin-1-yl)imidazo[1,2-b]pyridazin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(40 mg, 28%) was obtained as a yellow powder using a procedure analogousto that described in Step 6 of Example 117, substituting6-(1-methylpiperidin-4-yl)pyridazin-3-amine (Ref: U.S. Pat. No.4,104,385 A1, 1978) and2-chloro-3-(2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)propanalfrom Step 2 of Example 153, respectively, for 2-aminoisonicotinonitrileand 2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal used inExample 117. ¹H NMR (500 MHz, DMSO-d₆) δ 7.88 (d, J=7.4 Hz, 1H), 7.78(d, J=9.8 Hz, 1H), 7.58 (s, 1H), 7.33 (br s, 1H), 7.24 (d, J=7.9 Hz,1H), 7.13 (d, J=8.4 Hz, 1H), 7.10 (d, J=9.8 Hz, 1H), 4.77 (br s, 1H),4.16 (s, 2H), 3.44-3.51 (m, 4H), 3.34 (td, J=4.6, 9.0 Hz, 2H), 2.37-2.46(m, 4H), 2.21 (s, 3H), 1.98-2.08 (m, 1H), 1.87-1.94 (m, 1H), 1.53-1.70(m, 2H), 1.09-1.35 (m, 4H). LCMS (ESI) m/z 478 (M+H)⁺.

Example 179 Preparation of(trans-4-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)methanol

Step 1: To a stirred suspension of trans-4-aminocyclohexanecarboxylicacid hydrochloride (0.5 g, 2.8 mmol) in anhydrous THF (10 mL) at 0° C.under argon was added dropwise lithium aluminum hydride (2 M solution inTHF, 5.6 mL, 11 mmol). The mixture was stirred for 1 h at 0° C., thenallowed to warm to rt and stir for an additional 1 h. The mixture wasthen heated in a sealed tube at 85° C. for 12 h. The mixture was cooledto 0° C. and H₂O (600 μL) was slowly added, followed by a 1 M aq NaOH(1.2 mL) and H₂O (1.8 mL). The mixture was diluted with CH₂Cl₂ (50 mL)and stirred for 30 min at rt. The mixture was filtered, and the filtratewas concentrated under reduced pressure to afford(trans-4-aminocyclohexyl)methanol (323 mg, 90%) as a white solid thatdid not require further purification.

Step 2:(trans-4-((6-((6-Fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)methanolwas synthesized as a white powder (43 mg, 36%) using a procedureanalogous to that described in Step 5 of Example 162, substituting(trans-4-aminocyclohexyl)methanol for (1S,2R)-2-aminocyclohexanolhydrochloride used in Example 162. ¹H NMR (500 MHz, DMSO-d₆) δ 8.68 (s,1H), 8.41 (t, J=2.0 Hz, 1H), 8.07 (dd, J=2.6, 9.5 Hz, 1H), 7.95 (d,J=7.4 Hz, 1H), 7.66 (d, J=1.2 Hz, 1H), 7.31 (m, 1H), 7.22 (dd, J=1.6,8.2 Hz, 1H), 5.47 (s, 2H), 4.40 (t, J=5.2 Hz, 1H), 3.58 (m, 1H), 3.22(m, 2H), 2.00-2.07 (m, 2H), 1.73-1.80 (m, 2H), 1.32 (m, 1H), 1.13-1.25(m, 2H), 0.92-1.03 (m, 2H); LCMS (ESI) m/z 412 (M+H)⁺.

Example 180 Preparation of(cis-4-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)methanol

Step 1: (cis-4-Aminocyclohexyl)methanol was synthesized as a whitepowder (301 mg, 86%) using a procedure analogous to that described inStep 1 of Example 179, substituting cis-4-aminocyclohexanecarboxylicacid for trans-4-aminocyclohexanecarboxylic acid hydrochloride used inExample 179.

Step 2:(cis-4-((6-((6-Fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)methanolwas synthesized as a white powder (26 mg, 21%) using a procedureanalogous to that described in Step 5 of Example 162, substituting(cis-4-aminocyclohexyl)methanol from the previous step for(1S,2R)-2-aminocyclohexanol hydrochloride used in Example 162. ¹H NMR(500 MHz, DMSO-d₆) δ 8.67 (s, 1H), 8.41 (t, J=2.0 Hz, 1H), 8.07 (dd,J=2.5, 9.4 Hz, 1H), 7.98 (d, J=7.1 Hz, 1H), 7.66 (d, J=1.0 Hz, 1H), 7.30(m, 1H), 7.23 (dd, J=1.4, 8.2 Hz, 1H), 5.48 (s, 2H), 4.41 (t, J=4.9 Hz,1H), 3.96 (m, 1H), 3.26 (t, J=5.4 Hz, 2H), 1.70-1.78 (m, 2H), 1.4-1.60(m, 5H), 1.28-1.38 (m, 2H); LCMS (ESI) m/z 412 (M+H)⁺.

Example 181 Preparation of6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-N-((1R,2R)-2-(methylthio)cyclohexyl)benzo[d]thiazol-2-amine

Step 1: To a stirred mixture of(1R,2R)-2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(517 mg, 1.3 mmol) from Example 162, TEA (194 μL, 1.4 mmol), and CH₂Cl₂(15 mL) at rt under argon was added methanesulfonyl chloride (152 μL,2.0 mmol). After stirring the mixture for 15 h, additional TEA (194 μL,1.4 mmol) and methanesulfonyl chloride (152 μL, 2.0 mmol) were added.After stirring for an additional 18 h, the mixture was diluted withCH₂Cl₂ and stirred with saturated aq NaHCO₃ (50 mL) for 30 min. Thelayers were separated and the organic layer was washed with brine (50mL), dried over MgSO₄, filtered, and concentrated under reducedpressure. The residue was purified by silica gel flash chromatography,eluting with a gradient of 100% hexanes to 100% EtOAc, to afford(1S,2R)-2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexylmethanesulfonate (274 mg, 44%) as a clear oil. ¹H NMR (500 MHz, DMSO-d₆)δ 8.66 (s, 1H), 8.39 (t, J=1.8 Hz, 1H), 8.16 (d, J=7.4 Hz, 1H), 8.04(dd, J=2.6, 9.5 Hz, 1H), 7.66 (d, J=1.0 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H),7.22 (dd, J=1.4, 8.2 Hz, 1H), 5.46 (s, 2H), 4.98 (m, 1H), 4.06 (m, 1H),2.99 (s, 3H), 2.01 (m, 1H), 1.54-1.72 (m, 4H), 1.34-1.50 (m, 3H); LCMS(ESI) m/z 476 (M+H)⁺.

Step 2: A mixture of(1S,2R)-2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexylmethanesulfonate (100 mg, 0.2 mmol) and sodium thiomethoxide (74 mg, 1.0mmol) in DMF (1.0 mL) was stirred at rt for 2 h. The mixture waspurified directly by reverse-phase preparative HPLC using a mixture ofwater (5% CH₃CN, 0.05% HCOOH) and CH₃CN (0.05% HCOOH) as the mobilephase and Varian Pursuit XRs C18 column as the stationary phase toafford6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-N-((1R,2R)-2-(methylthio)cyclohexyl)benzo[d]thiazol-2-amine(5 mg, 4%) as a white powder. ¹H NMR (500 MHz, DMSO-d₆) δ 8.68 (s, 1H),8.41 (t, J=1.8 Hz, 1H), 8.04-8.11 (m, 2H), 7.67 (s, 1H), 7.30 (m, 1H),7.23 (m, 1H), 5.48 (s, 2H), 3.72 (m, 1H), 2.56 (m, 1H), 1.99-2.08 (m,5H), 1.63-1.71 (m, 2H), 1.41-1.51 (m, 1H), 1.21-1.36 (m, 3H); LCMS (ESI)m/z 428 (M+H)⁺.

Example 182 Preparation of(1R,2R)-2-((6-((5-(oxetan-3-yloxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: To a stirred mixture of oxetan-3-ol (0.85 g, 11.5 mmol) in DCM(38 mL) were added TEA (3.3 mL, 23 mmol) and 4-methylbenzene-1-sulfonylchloride (2.7 g, 13.8 mmol). The reaction mixture was stirred at rt for15 h. The mixture was partitioned between water and DCM. The organiclayer was separated, dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by silica gel flashchromatography eluting with a gradient of 30% DCM in petroleum ether to100% DCM to afford oxetan-3-yl 4-methylbenzenesulfonate (1.3 g, 50%) asa white solid. ¹H NMR (300 MHz, CDCl₃) δ 7.77 (d, J=8.4 Hz, 2H), 7.35(d, J=8.7 Hz, 2H), 5.30 (m, 1H), 4.66-4.74 (m, 4H), 2.46 (s, 3H); LCMS(ESI) m/z 229 (M+H)⁺.

Step 2: A stirred mixture of1-((2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-ol (100 mg,0.23 mmol) from Step 1 of Example 171, oxetan-3-yl4-methylbenzenesulfonate (420 mg, 1.84 mmol) from the previous step,Cs₂CO₃ (225 mg, 0.69 mmol), sodium iodide (276 mg, 0.69 mmol) and NMP (4mL) was heated at 145° C. for 15 h. The mixture was diluted with EtOAcand washed with brine. The organic layer was dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by silica gel flash chromatography eluting with 40:1 DCM/MeOHto afford(3aR,7aR)-2,2-dimethyl-3-(6-((5-(oxetan-3-yloxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)octahydrobenzo[d]oxazole(35 mg, 31%) as a yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 7.90 (s, 1H),7.58 (d, J=8.4 Hz, 1H), 7.40 (s, 1H), 7.17-7.20 (m, 2H), 6.94 (s, 1H),6.84 (m, 1H), 5.35 (s, 2H), 5.24 (m, 1H), 5.00 (m, 2H), 4.79 (m, 2H),3.66 (m, 1H), 3.08 (m, 1H), 2.81 (m, 1H), 2.15 (m, 1H), 1.84-1.92 (m,2H), 1.78 (s, 3H), 1.63 (s, 3H), 1.30-1.45 (m, 4H); LCMS (ESI) m/z 491(M+H)⁺.

Step 3:(1R,2R)-2-((6-((5-(Oxetan-3-yloxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(20 mg, 50%) was obtained as a yellow solid using a procedure analogousto that described in Step 2 of Example 172, substituting(3aR,7aR)-2,2-dimethyl-3-(6-((5-(oxetan-3-yloxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)octahydrobenzo[d]oxazolefrom Step 2 of this Example for2-((1-((2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)oxy)ethanolused in Example 172. ¹H NMR (300 MHz, DMSO-d₆) δ 8.21 (s, 1H), 7.49 (s,1H), 7.34-7.37 (m, 2H), 7.19 (m, 1H), 6.82-6.89 (m, 2H), 5.44 (s, 2H),5.28 (t, J=8.4 Hz, 1H), 5.00-5.04 (m, 2H), 4.67-4.71 (m, 2H), 3.57 (m,1H), 3.44 (m, 1H), 2.08 (m, 1H), 2.00 (m, 1H), 1.70-1.77 (m, 2H),1.29-1.41 (m, 4H); LCMS (ESI) m/z 451 (M+H)⁺.

Example 183 Preparation of(1R,2R)-2-((6-((5-vinyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1:4-Iodo-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroaniline(5.7 g, 66%) was obtained as a yellow solid using a procedure analogousto that described in Step 1 of Example 127, substituting4-iodo-2-nitroaniline for 4-methyl-2-nitroaniline used in Example 127.¹H NMR (300 MHz, CDCl₃) δ 8.50 (d, J=2.1 Hz, 1H), 8.46 (br s, 1H), 7.85(d, J=8.7 Hz, 1H), 7.70 (s, 1H), 7.57 (d, J=9.0 Hz, 1H), 7.36 (d, J=8.4Hz, 1H), 6.58 (d, J=9.0 Hz, 1H), 4.63 (d, J=5.7 Hz, 2H), 2.79 (s, 3H);LCMS (ESI) m/z 458 (M+H)²⁺.

Step 2:4-Iodo-N¹-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine(4.89 g, 92%) was obtained as a yellow solid using a procedure analogousto that described in Step 2 of Example 129, substituting4-iodo-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroanilinefrom Step 1 of this Example for4-fluoro-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroanilineused in Example 129. LCMS (ESI) m/z 428 (M+H)⁺.

Step 3:6-((5-Iodo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole(3 g, 60%) was obtained as a orange solid using a procedure analogous tothat described in Step 3 of Example 130, substituting4-iodo-N¹-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diaminefrom Step 2 of this Example forN¹-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-4-(trifluoromethyl)benzene-1,2-diamineused in Example 130. ¹H NMR (300 MHz, CDCl₃) δ 8.18 (s, 1H), 7.91 (s,1H), 7.82 (d, J=8.4 Hz, 1H), 7.48-7.53 (m, 2H), 7.24 (d, J=9.0 Hz, 1H),7.04 (d, J=8.4 Hz, 1H), 5.43 (s, 2H), 2.78 (s, 3H); LCMS (ESI) m/z 438(M+H)⁺.

Step 4:6-((5-Iodo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole(2.79 g, 90%) was obtained as a tan solid using a procedure analogous tothat described in Step 4 of Example 130, substituting6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazolefrom Step 3 of this Example for2-(methylthio)-6-((5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazoleused in Example 130. ¹H NMR (300 MHz, CDCl₃) δ 8.20 (s, 1H), 8.03 (d,J=8.4 Hz, 1H), 7.96 (s, 1H), 7.76 (s, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.36(d, J=8.4 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 5.51 (s, 2H), 3.07 (s, 3H);LCMS (ESI) m/z 454 (M+H)⁺.

Step 5:(1R,2R)-2-((6-((5-Iodo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(1.78 g, 57%) was obtained as a brown solid using a procedure analogousto that described in Step 5 of Example 130, substituting6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazolefrom Step 4 of this Example for2-(methylsulfinyl)-6-((5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazoleused in Example 130. ¹H NMR (300 MHz, CDCl₃) δ 8.13 (s, 1H), 7.87 (s,1H), 7.46 (d, J=8.45 Hz, 1H), 7.44 (d, J=9.9 Hz, 1H), 7.19 (s, 1H), 7.08(d, J=8.4 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 5.28 (s, 2H), 3.52 (m, 1H),3.44 (m, 1H), 2.04-2.16 (m, 2H), 1.68-2.73 (m, 2H), 1.18-1.42 (m, 4H);LCMS (ESI) m/z 505 (M+H)⁺.

Step 6:(1R,2R)-2-((6-((5-Vinyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(64 mg, 20%) was obtained as a white solid using a procedure analogousto that described in Example 174, substituting4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane for2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneused in Example 174. ¹H NMR (300 MHz, DMSO-d₆) δ 8.39 (s, 1H), 7.95 (d,J=7.5 Hz, 1H), 7.72 (s, 1H), 7.64 (s, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.38(d, J=8.4 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 6.81(m, 1H), 5.77 (d, J=18.0 Hz, 1H), 5.45 (s, 2H), 5.16 (d, J=11.1 Hz, 1H),4.73 (d, J=8.4 Hz, 1H), 3.53 (m, 1H), 3.27 (m, 1H), 2.02 (m, 1H), 1.87(m, 1H), 1.60-1.62 (m, 2H), 1.20-1.24 (m, 4H); LCMS (ESI) m/z 405(M+H)⁺.

Example 184 Preparation of(1R,2R)-2-((6-((5-(cyclohex-1-en-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

(1R,2R)-2-((6-((5-(Cyclohex-1-en-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(80 mg, 30%) was obtained as a white solid using a procedure analogousto that described in Example 174, substituting 2-(cyclohex-1-en-1-yl)-4,4, 5, 5-tetramethyl-1,3,2-dioxaborolane for2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneused in Example 174. ¹H NMR (300 MHz, DMSO-d₆) δ 8.35 (s, 1H), 7.94 (d,J=8.1 Hz, 1H), 7.60 (d, J=8.7 Hz, 2H), 7.45 (d, J=8.4 Hz, 1H), 7.29 (d,J=8.1 Hz, 2H), 7.18 (m, 1H), 6.08 (d, J=4.5 Hz, 1H), 5.44 (s, 2H), 4.72(d, J=5.4 Hz, 1H), 3.51 (m, 1H), 3.37 (m, 1H), 2.39-2.45 (m, 2H),2.13-2.20 (m, 2H), 2.04 (m, 1H), 1.89 (m, 1H), 1.80-1.83 (m, 2H),1.56-1.66 (m, 4H), 1.11-1.36 (m, 4H); LCMS (ESI) m/z 459 (M+H)⁺.

Example 185 Preparation of(1R,2R)-2-((6-((5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

(1R,2R)-2-((6-((5-(1-Methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(71 mg, 25%) was obtained as a white solid using a procedure analogousto that described in Example 174, substituting(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)boronic acid for2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneused in Example 174. ¹H NMR (300 MHz, DMSO-d₆) δ 8.44 (s, 1H), 8.10 (s,1H), 7.95 (m, 1H), 7.69 (s, 1H), 7.63 (s, 1H), 7.60 (d, J=8.7 Hz, 1H),7.30 (d, J=8.4 Hz, 1H), 7.23-7.75 (m, 2H), 5.48 (s, 2H), 4.70 (m, 1H),3.96 (s, 3H), 3.51 (m, 1H), 3.32 (m, 1H), 2.03 (m, 1H), 1.84 (m, 1H),1.59-1.62 (m, 2H), 1.15-1.29 (m, 4H); LCMS (ESI) m/z 527 (M+H)⁺.

Example 186 Preparation of(1R,2R)-2-((6-((5-fluoroimidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

(1R,2R)-2-((6-((5-Fluoroimidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(5 mg, 10%) was obtained as a yellow powder using a procedure analogousto that described in Step 6 of Example 117, substituting6-fluoropyridin-2-amine and2-chloro-3-(2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)propanalfrom Step 2 of Example 153, respectively, for 2-aminoisonicotinonitrileand 2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal used inExample 117. ¹H NMR (500 MHz, DMSO-d₆) δ 7.92 (d, J=7.4 Hz, 1H), 7.42(d, J=3.9 Hz, 1H), 7.35-7.40 (m, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.22 (dd,J=7.1, 15.5 Hz, 1H), 6.99 (d, J=7.9 Hz, 1H), 6.66 (t, J=7.1 Hz, 1H),4.80 (br s, 1H), 4.39 (br s, 2H), 3.50 (br s, 2H), 2.04 (d, J=11.8 Hz,1H), 1.87 (d, J=10.8 Hz, 1H), 1.54-1.70 (m, 2H), 1.10-1.37 (m, 4H). LCMS(ESI) m/z 397 (M+H)⁺.

Example 187 Preparation of(1R,2R)-2-((6-((7-morpholinoimidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: A mixture of 4-chloropyridin-2-amine (400 mg, 3.1 mmol) andmorpholine (2 mL) in 2 mL of DMA was heated at 200° C. for 5 min in amicrowave reactor. LCMS analysis indicated completion of the reaction.The mixture was partitioned between EtOAc and brine, and the organiclayer was dried over Na₂SO₄ and concentrated under reduced pressure togive crude 4-morpholinopyridin-2-amine as a yellow solid (350 mg). LCMS(ESI) m/z 180 (M+H)⁺.

Step 2:(1R,2R)-2-((6-((7-Morpholinoimidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(50 mg, 31%) was obtained as a yellow powder using a procedure analogousto that described in Step 6 of Example 117, substituting4-morpholinopyridin-2-amine from Step 1 of this Example and2-chloro-3-(2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)propanalfrom Step 2 of Example 153, respectively, for 2-aminoisonicotinonitrileand 2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal used inExample 117. ¹H NMR (500 MHz, DMSO-d₆) δ 7.94 (d, J=7.9 Hz, 1H), 7.88(d, J=7.4 Hz, 1H), 7.48 (s, 1H), 7.25 (d, J=7.9 Hz, 1H), 7.18 (s, 1H),7.06 (d, J=8.4 Hz, 1H), 6.79 (dd, J=2.2, 7.6 Hz, 1H), 6.67 (d, J=2.0 Hz,1H), 4.75 (br s, 1H), 4.20 (s, 2H), 3.67-3.79 (m, 4H), 3.50 (br s, 2H),3.09-3.16 (m, 4H), 2.03 (d, J=11.8 Hz, 1H), 1.86 (br s, 1H), 1.55-1.71(m, 2H), 1.12-1.38 (m, 4H). LCMS (ESI) m/z 464 (M+H)⁺.

Example 188 Preparation of(1R,2R)-2-((6-((7-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: A mixture of 4-chloropyridin-2-amine (400 mg, 3.1 mmol) andN-methylpiperizine (2 mL) in DMA (2 mL) was heated at 200° C. for 5 minin a microwave reactor. LCMS analysis indicated completion of thereaction. The reaction mixture was partitioned between EtOAc and brine,and the organic layer was dried over Na₂SO₄ and concentrated underreduced pressure to give crude 4-(4-methylpiperazin-1-yl)pyridin-2-amineas a brown solid (350 mg). LCMS (ESI) m/z 193 (M+H)⁺.

Step 2:(1R,2R)-2-((6-((7-(4-Methylpiperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(17 mg, 9%) was obtained as a yellow solid using a procedure analogousto that described in Step 6 of Example 117, substituting4-(4-methylpiperazin-1-yl)pyridin-2-amine from Step 1 of this Example,and2-chloro-3-(2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)propanalfrom Step 2 of Example 153, respectively, for 2-aminoisonicotinonitrileand 2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal used inExample 117. ¹H NMR (500 MHz, DMSO-d₆) δ 7.90 (d, J=7.4 Hz, 1H), 7.87(d, J=7.4 Hz, 1H), 7.47 (s, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.17 (s, 1H),7.06 (d, J=6.9 Hz, 1H), 6.72-6.81 (m, 2H), 6.64 (s, 1H), 4.19 (s, 2H),3.51 (br s, 1H), 3.31-3.37 (m, 2H), 3.16 (d, J=4.4 Hz, 4H), 2.42 (d,J=4.4 Hz, 4H), 2.21 (s, 3H), 2.03 (d, J=11.8 Hz, 1H), 1.83-1.87 (m, 1H),1.55-1.70 (m, 2H), 1.10-1.35 (m, 4H). LCMS (ESI) m/z 477 (M+H)⁺.

Example 189 Preparation of((1R,2R)-2-((6-((5,7-dimethyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: N-(2,4-Dimethyl-6-nitrophenyl)formamide (746 mg, 64%) wasobtained as a solid using a procedure analogous to that described inStep 1 of Example 203, substituting 4,6-dimethyl-2-nitroaniline for4-bromo-2-fluoro-6-nitroaniline used in Example 203. LCMS (ESI) m/z 195(M+H)⁺.

Step 2:N-(2,4-Dimethyl-6-nitrophenyl)-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)formamide(1.29 g, 87%) was obtained as a yellow solid using a procedure analogousto that described in Step 2 of Example 203, substitutingN-(2,4-dimethyl-6-nitrophenyl)formamide from the previous step forN-(4-bromo-2-fluoro-6-nitrophenyl)formamide used in Example 203. LCMS(ESI) m/z 388 (M+H)⁺.

Step 3:6-((5,7-Dimethyl-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole(696 mg, 62%) was obtained as a solid using a procedure analogous tothat described in Step 3 of Example 203, substitutingN-(2,4-dimethyl-6-nitrophenyl)-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)formamidefrom the previous step forN-(4-bromo-2-fluoro-6-nitrophenyl)-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)formamideused in Example 203. ¹H NMR (500 MHz, DMSO-d₆) δ 8.25 (s, 1H), 7.80 (d,J=8.4 Hz, 1H), 7.60 (d, J=0.8 Hz, 1H), 7.29 (s, 1H), 7.08 (dd, J=8.4,1.6 Hz, 1H), 6.74 (s, 1H), 5.75 (s, 2H), 2.75 (s, 3H), 2.33 (s, 3H),2.33 (s, 3H); LCMS (ESI) m/z 340 (M+H)⁺.

Step 4:6-((5,7-Dimethyl-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole(600 mg, 83%) was obtained as a solid using a procedure analogous tothat described in Step 4 of Example 203, substituting6-((5,7-dimethyl-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazolefrom the previous step for6-((5-bromo-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazoleused in Example 203. ¹H NMR (500 MHz, DMSO-d₆) δ 8.28 (s, 1H), 8.07 (d,J=8.5 Hz, 1H), 7.83 (m, 1H), 7.31 (m, 1H), 7.28 (dd, J=8.6, 1.6 Hz, 1H),6.74 (m, 1H), 5.83 (s, 2H), 3.05 (s, 3H), 2.33 (s, 3H), 2.33 (s, 3H);LCMS (ESI) m/z 356 (M+H)⁺.

Step 5:((1R,2R)-2-((6-((5,7-Dimethyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(50 mg, 29%) was obtained as a solid using a procedure analogous to thatdescribed in Step 5 of Example 203, substituting6-((5,7-dimethyl-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole from the previous step for6-((5-bromo-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole used in Example 203. ¹H NMR (500 MHz, DMSO-d₆)δ 8.21 (s, 1H), 7.96 (d, J=7.6 Hz, 1H), 7.22-7.30 (m, 3H), 6.81 (dd,J=1.2, 8.4 Hz, 1H), 6.73 (s, 1H), 5.62 (s, 2H), 4.75 (br m, 1H), 3.51(br m, 1H), 3.30 (br m, 1H), 2.38 (s, 3H), 2.33 (s, 3H), 2.02 (m, 1H),1.85 (m, 1H), 1.56-1.66 (m, 2H), 1.13-1.30 (m, 4H); LCMS (ESI) m/z 407(M+H)⁺.

Example 190 Preparation of(1R,2R)-2-((6-((5-bromo-7-methyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: N-(4-bromo-2-methyl-6-nitrophenyl)formamide (227 mg, 33%) wasobtained as a solid using a procedure analogous to that described inStep 1 of Example 203, substituting 4-bromo-2-methyl-6-nitroaniline for4-bromo-2-fluoro-6-nitroaniline used in Example 203. LCMS (ESI) m/z 259and 260 (M+H)⁺.

Step 2:N-(4-Bromo-2-methyl-6-nitrophenyl)-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)formamide(377 mg, 95%) was obtained as an oil using a procedure analogous to thatdescribed in Step 2 of Example 203, substitutingN-(4-bromo-2-methyl-6-nitrophenyl)formamide from the previous step forN-(4-bromo-2-fluoro-6-nitrophenyl)formamide used in Example 203. LCMS(ESI) m/z 452 and 454 (M+H)⁺.

Step 3:6-((5-Bromo-7-methyl-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole(100 mg, 30%) was obtained as a solid using a procedure analogous tothat described in Step 3 of Example 203, substitutingN-(4-bromo-2-methyl-6-nitrophenyl)-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)formamidefrom the previous step forN-(4-bromo-2-fluoro-6-nitrophenyl)-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)formamideused in Example 203. ¹H NMR (500 MHz, DMSO-d₆) δ 8.38 (s, 1H), 7.81 (d,J=8.4 Hz, 1H), 7.72 (m, 1H), 7.62 (m, 1H), 7.10-7.11 (m, 2H), 5.79 (s,2H), 2.76 (s, 3H), 2.37 (s, 3H); LCMS (ESI) m/z 404 and 406 (M+H)⁺.

Step 4:6-((5-Bromo-7-methyl-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole(60 mg, 58%) was obtained as a solid using a procedure analogous to thatdescribed in Step 4 of Example 203, substituting6-((5-bromo-7-methyl-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazolefrom the previous step for6-((5-bromo-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazoleused in Example 203. ¹H NMR (500 MHz, DMSO-d₆) δ 8.42 (s, 1H), 8.09 (d,J=8.5 Hz, 1H), 7.85 (m, 1H), 7.73 (m, 1H), 7.31 (dd, J=8.6, 1.6 Hz, 1H),7.12 (m, 1H), 5.87 (s, 2H), 3.05 (s, 3H), 2.37 (s, 3H); LCMS (ESI) m/z420 and 422 (M+H)⁺.

Step 5:(1R,2R)-2-((6-((5-Bromo-7-methyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(9 mg, 13%) was obtained as a solid using a procedure analogous to thatdescribed in Step 5 of Example 203, substituting6-((5-bromo-7-methyl-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole from the previous step for6-((5-bromo-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole used in Example 203. ¹H NMR (500 MHz, DMSO-d₆)δ 8.34 (s, 1H), 7.98 (d, J=7.6 Hz, 1H), 7.70 (d, J=1.0 Hz, 1H),7.25-7.31 (m, 2H), 7.10 (s, 1H), 6.83 (dd, J=1.2, 8.1 Hz, 1H), 5.66 (s,2H), 4.76 (br m, 1H), 3.51 (br m, 1H), 3.30 (br m, 1H), 2.42 (s, 3H),2.03 (m, 1H), 1.87 (m, 1H), 1.56-1.66 (m, 2H), 1.13-1.32 (m, 4H); LCMS(ESI) m/z 471 and 473 (M+H)⁺.

Example 191 Preparation of6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-N-phenylbenzo[d]thiazol-2-amine

6-((6-Fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-N-phenylbenzo[d]thiazol-2-aminewas synthesized as a white powder (38 mg, 23%) using a procedureanalogous to that described in Step 5 of Example 162, substitutinganiline for (1S,2R)-2-aminocyclohexanol hydrochloride used in Example162 and increasing the reaction temperature to 130° C. ¹H NMR (500 MHz,DMSO-d₆) δ 10.50 (br s, 1H), 8.71 (s, 1H), 8.42 (m, 1H), 8.09 (dd,J=2.5, 9.4 Hz, 1H), 7.80 (s, 1H), 7.73-7.77 (m, 2H), 7.55 (d, J=8.4 Hz,1H), 7.32-7.37 (m, 3H), 7.01 (t, J=7.4 Hz, 1H), 5.55 (s, 2H); LCMS (ESI)m/z 376 (M+H)⁺.

Example 192 Preparation of((1R,3R)-3-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)methanol

Step 1: A mixture of(1R,3R)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid in a1:1 solution of TFA: CH₂Cl₂ (6 mL) was stirred at rt for 3 h. Themixture was concentrated under reduced pressure. The residue wastriturated in ethyl ether (50 mL) and the resulting solid was collectedby filtration to afford (1R,3R)-3-aminocyclohexanecarboxylic acidtrifluoroacetate (253 mg, 86%) as a white solid that did not requirefurther purification.

Step 2: ((1R,3R)-3-Aminocyclohexyl)methanol was synthesized as a whitepowder (213 mg, 75%) using a procedure analogous to that described inStep 1 of Example 179, substituting (1R,3R)-3-aminocyclohexanecarboxylicacid trifluoroacetate from the previous step fortrans-4-aminocyclohexanecarboxylic acid hydrochloride used in Example179.

Step 3:((1R,3R)-3-((6-((6-Fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)methanolwas synthesized as a white powder (17 mg, 10%) using a procedureanalogous to that described in Step 5 of Example 162, substituting((1R,3R)-3-aminocyclohexyl)methanol from the previous step for(1S,2R)-2-aminocyclohexanol hydrochloride used in Example 162. ¹H NMR(500 MHz, DMSO-d₆) δ 8.68 (s, 1H), 8.41 (t, J=1.8 Hz, 1H), 8.07 (dd,J=2.5, 9.4 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H), 7.66 (s, 1H), 7.31 (m, 1H),7.23 (dd, J=1.5, 8.4 Hz, 1H), 5.48 (s, 2H), 4.43 (m 1H), 3.65 (m, 1H),3.17-3.28 (m, 2H), 1.95-2.10 (m, 2H), 1.61-1.79 (m, 2H), 1.49 (m, 1H),1.31 (m, 1H), 1.08 (m, 1H), 0.75-0.90 (m, 2H); LCMS (ESI) m/z 412(M+H)⁺.

Example 193 Preparation of(1R,2S,3R)-3-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol

(1R,2S,3R)-3-((6-((6-Fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diolwas synthesized as a white powder (15 mg, 14%) using a procedureanalogous to that described in Step 5 of Example 232, substituting6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazolefrom Step 4 of Example 70 for6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazoleused in Example 232. ¹H NMR (500 MHz, DMSO-d₆) δ 8.68 (s, 1H), 8.41 (t,J=2.0 Hz, 1H), 8.07 (dd, J=2.5, 9.4 Hz, 1H), 7.94 (d, J=7.9 Hz, 1H),7.66 (d, J=1.0 Hz, 1H), 7.29 (m, 1H), 7.22 (dd, J=1.4, 8.2 Hz, 1H), 5.48(s, 2H), 4.54 (br s, 1H), 4.44 (br s, 1H), 3.93 (m, 1H), 3.79 (m, 1H),3.39 (m, 1H), 1.91 (m, 1H), 1.52-1.69 (m, 2H), 1.33-1.43 (m, 2H), 1.19(m, 1H); LCMS (ESI) m/z 414 (M+H)⁺.

Example 194 Preparation of((1S,3R)-3-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)methanol

Step 1: (1S,3R)-3-Aminocyclohexanecarboxylic acid trifluoroacetate wassynthesized as a white powder (275 mg, 94%) using a procedure analogousto that described in Step 1 of Example 192, substituting(1S,3R)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid for(1R,3R)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid used inExample 192.

Step 2: ((1S,3R)-3-Aminocyclohexyl)methanol was synthesized as a whitepowder (157 mg, 59%) using a procedure analogous to that described inStep 1 of Example 179, substituting (1S,3R)-3-aminocyclohexanecarboxylicacid trifluoroacetate from the previous step fortrans-4-aminocyclohexanecarboxylic acid hydrochloride used in Example179.

Step 3:((1S,3R)-3-((6-((6-Fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)methanolwas synthesized as a white powder (15 mg, 8%) using a procedureanalogous to that described in Step 5 of Example 162, substituting((1S,3R)-3-aminocyclohexyl)methanol from the previous step for(1S,2R)-2-aminocyclohexanol hydrochloride used in Example 162. ¹H NMR(500 MHz, DMSO-d₆) δ 8.68 (s, 1H), 8.41 (t, J=1.8 Hz, 1H), 8.07 (dd,J=2.5, 9.4 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H), 7.66 (s, 1H), 7.31 (m, 1H),7.23 (dd, J=1.5, 8.4 Hz, 1H), 5.48 (s, 2H), 4.43 (m 1H), 3.65 (m, 1H),3.17-3.28 (m, 2H), 1.95-2.10 (m, 2H), 1.61-1.79 (m, 2H), 1.49 (m, 1H),1.31 (m, 1H), 1.08 (m, 1H), 0.75-0.90 (m, 2H); LCMS (ESI) m/z 412(M+H)⁺.

Example 195 Preparation of6-chloro-1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]oxazol-6-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

Step 1: A mixture of 5-chloro-2-nitroaniline (6.0 g, 34.88 mmol) and NBS(6.06 g, 34.0 mmol) in HOAc (240 mL) was stirred at 130° C. for 1 h. Thereaction mixture was poured into water. The precipitate was collected byfiltration and washed with petroleum ether to give4-bromo-5-chloro-2-nitroaniline as a light brown solid (8.25 g, 96.5%).¹H NMR (300 MHz, DMSO-d₆) δ 8.24 (s, 1H), 7.62 (br s, 2H), 7.29 (s, 1H).LCMS (ESI) m/z 251 (M+H)⁺.

Step 2: To a solution of 4-bromo-5-chloro-2-nitroaniline (550 mg, 2.19mmol) from the previous step and TFA (2.26 mL) in DCM (10 mL) at −15° C.was added NaBH(OAc)₃ (1.39 g, 5.37 mmol). Then a solution of2-(methylthio)benzo[d]oxazole-6-carbaldehyde (465 mg, 2.41 mmol) in DCM(6 mL) was added to the mixture. After complete addition, the mixturewas stirred at −10° C. to 0° C. for 2 h. The reaction mixture wasdiluted with DCM and washed sequentially with H₂O, aq NaHCO₃ and brine.The organic layer was dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by silica gel chromatographyeluting with 5:1 to 2:1 petroleum ether/DCM to give4-bromo-5-chloro-N-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)-2-nitroanilineas a yellow solid (451 mg, 48.2%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.81 (t,1H), 8.34 (s, 1H), 7.66 (s, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.37 (d, J=6.9Hz, 1H), 7.19 (s, 1H), 4.76 (d, J=6.3 Hz, 2H), 2.74 (s, 3H). LCMS (ESI)m/z 428 (M+H)⁺.

Step 3: To a stirred solution of4-bromo-5-chloro-N-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)-2-nitroaniline(451 mg, 1.06 mmol) in methanol (80 mL) and DCM (80 mL) was addedpalladium on activated charcoal (100 mg). The mixture was stirred underhydrogen for 2 h, filtered and concentrated under reduced pressure togive4-bromo-5-chloro-N¹-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)benzene-1,2-diamineas a light yellow solid (415 mg, 98.6%). ¹H NMR (300 MHz, DMSO-d₆) δ7.57-7.60 (m, 2H), 7.35 (d, J=8.1 Hz, 1H), 6.81 (s, 1H), 6.41 (s, 1H),5.64 (t, 1H), 5.03 (s, 2H), 4.40 (d, J=6.0 Hz, 2H), 2.74 (s, 3H). LCMS(ESI) m/z 399 (M+H)⁺.

Step 4: A mixture of4-bromo-5-chloro-N-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)benzene-1,2-diamine(622 mg, 2.40 mmol), triethoxymethane (5 mL) and HCOOH (0.08 mL) wasstirred at 90° C. for 2 h. The reaction mixture was concentrated underreduced pressure. The residue was purified by silica gel chromatography,eluting with 1:1 petroleum ether/ethyl acetate to give6-((5-bromo-6-chloro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]oxazoleas a light brown solid (607 mg, 84.5%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.56(s, 1H), 8.07 (s, 1H), 8.02 (s, 1H), 7.72 (s, 1H), 7.60 (d, J=8.4 Hz,1H), 7.34 (d, J=6.6 Hz, 1H), 5.60 (s, 2H), 2.73 (s, 3H). LCMS (ESI) m/z408 (M+H)⁺.

Step 5: A solution of6-((5-bromo-6-chloro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]oxazole(554 mg, 1.80 mmol) and m-CPBA (403 mg, 2.34 mmol) in DCM (18 mL) wasstirred at 0° C. for 3 h. The reaction mixture was washed with aqueousNa₂S₂O₃ and brine. The organic layer was dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography eluting with 1:5 petroleum ether/ethyl acetate togive6-((5-bromo-6-chloro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole(510 mg, 87.5%) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.59 (s,1H), 8.08 (s, 1H), 8.04 (s, 1H), 7.97 (s, 1H), 7.90 (d, J=8.7 Hz, 1H),7.50 (d, J=9.3 Hz, 1H), 5.69 (s, 2H), 3.18 (s, 3H). LCMS (ESI) m/z 424(M+H)⁺.

Step 6: A mixture of6-((5-bromo-6-chloro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole(460 mg, 1.08 mmol), (1R,2R)-2-aminocyclohexanol (245 mg, 2.13 mmol) andDIEA (366 mg, 2.84 mmol) in DMA (10 mL) was stirred at 120° C. for 1 h.The reaction mixture was cooled to rt, poured into water (30 mL) andextracted with ethyl acetate (100 mL×3). The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by silica gelchromatography eluting with 1:5 petroleum ether/ethyl acetate to give(1R,2R)-2-((6-((5-bromo-6-chloro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanolas a light yellow solid (470 mg, 82.3%). ¹H NMR (300 MHz, CDCl₃) δ 8.52(s, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.41 (s,1H), 7.14 (s, 1H), 5.48 (s, 2H), 4.68 (d, J=4.2 Hz, 1H), 3.33 (br s,2H), 1.91 (br s, 2H), 1.63 (br s, 2H), 1.25 (br s, 4H). LCMS (ESI) m/z477 (M+H)⁺.

Step 7: A mixture of(1R,2R)-2-((6-((5-bromo-6-chloro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol(215 mg, 0.45 mmol), Zn(CN)₂ (327 mg, 2.71 mmol), Pd₂(dba)₃ (82 mg, 0.09mmol) and dppf (100 mg, 0.18 mmol) in DMA (10 mL) was stirred at 100° C.for 16 h. The reaction mixture was cooled to room temperature, pouredinto water (20 mL) and extracted with ethyl acetate (50 mL×2). Thecombined organic layers were washed with water and brine, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by preparative HPLC to give6-chloro-1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]oxazol-6-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrileas a white solid (25 mg, 13.5%). ¹H NMR (300 MHz, DMSO-d₆): δ 8.69 (s,1H), 8.36 (s, 1H), 8.13 (s, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.45 (s, 1H),7.16 (s, 1H), 5.53 (s, 2H), 4.68 (d, J=4.5 Hz, 1H), 3.38-3.31 (m, 2H),1.92-1.86 (m, 2H), 1.65-1.60 (m, 2H), 1.27-1.19 (m, 4H). LCMS (ESI) m z422 (M+H)⁺.

Example 196 Preparation of2-((1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)oxy)acetonitrile

Step 1: 2-((1-((2-((3aR,7aR)-2,2-Dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)oxy)acetonitrile(42 mg, 25%) was obtained as a yellow solid using a procedure analogousto that described in Step 3 of Example 171, substitutingiodoacetonitrile for 4-(2-iodoethyl)morpholine used in Example 171. ¹HNMR (300 MHz, CDCl₃) δ 07.99 (s, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.30-7.40(m, 2H), 7.16-7.26 (m, 2H), 6.95 (m, 1H), 5.38 (s, 2H), 4.79 (s, 2H),3.65 (m, 1H), 3.08 (m, 1H), 2.80 (m, 1H), 2.17 (m, 1H), 1.82-1.92 (m,2H), 1.78 (s, 3H), 1.64 (s, 3H), 1.33-1.39 (m, 4H).

Step 2:2-((1-((2-(((1R,2R)-2-Hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)oxy)acetonitrile(31 mg, 68%) was obtained as a white solid using a procedure analogousto that described in Step 4 of Example 171, substituting2-((1-((2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)oxy)acetonitrilefor(3aR,7aR)-2,2-dimethyl-3-(6-((5-(2-morpholinoethoxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)octahydrobenzo[d]oxazoleused in Example 171. ¹H NMR (300 MHz, CDCl₃) δ □7.95 (s, 1H), 7.48 (d,J=8.4 Hz, 1H), 7.40 (d, J=2.1 Hz, 1H), 7.29 (m, 1H), 7.20 (d, J=8.1 Hz,1H), 7.16 (dd, J=8.1, 1.5 Hz, 1H), 6.96 (dd, J=8.7, 2.4 Hz, 1H), 5.36(s, 2H), 5.21 (m, 1H), 4.80 (s, 2H), 3.83 (br m, 1H), 3.61 (br m, 1H),3.47 (m, 1H), 2.08-2.18 (m, 2H), 1.75-1.79 (m, 2H), 1.24-1.44 (m, 4H).LCMS (ESI) m/z 434 (M+H)⁺.

Example 197 Preparation of6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-N-(2-methoxyphenyl)benzo[d]thiazol-2-amine

6-((6-Fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-N-(2-methoxyphenyl)benzo[d]thiazol-2-aminewas synthesized as a white powder (45 mg, 15%) using a procedureanalogous to that described in Example 191, substituting2-methoxyaniline for aniline used in Example 191. ¹H NMR (500 MHz,CDCl₃) δ 9.84 (s, 1H), 8.71 (s, 1H), 8.35-8.46 (m, 2H), 8.08 (dd, J=2.6,9.5 Hz, 1H), 7.78 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.31 (dd, J=1.5, 8.4Hz, 1H), 6.91-7.10 (m, 3H), 5.53 (s, 2H), 3.85 (s, 3H); LCMS (ESI) m/z407 (M+H)⁺.

Example 198 Preparation ofN-((1R,2R)-2-chlorocyclohexyl)-6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-amine

To a stirred mixture of(1S,2R)-2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(282 mg, 0.7 mmol) from Example 162, DIEA (247 μL, 1.4 mmol), and CH₂Cl₂(15 mL) at 0° C. under argon was added sulfuryl chloride (142 mg, 2.0mmol). The mixture was warmed to rt and stirred for 15 h, and thenstirred at 60° C. for 15 h. The mixture was cooled to rt and purifieddirectly by reverse-phase preparative HPLC using a mixture of water (5%CH₃CN, 0.05% HCOOH) and CH₃CN (0.05% HCOOH) as the mobile phase andVarian Pursuit XRs C18 column as the stationary phase. The product wasfurther purified by triturating in CH₂Cl₂ (5 mL) to affordN-((1R,2R)-2-chlorocyclohexyl)-6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-amine(29 mg, 10%) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ 8.68 (s, 1H),8.41 (s, 1H), 8.24 (d, J=8.4 Hz, 1H), 8.07 (dd, J=2.6, 9.5 Hz, 1H), 7.68(s, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.24 (dd, J=1.4, 8.2 Hz, 1H), 5.48 (s,2H), 4.02 (m, 1H), 3.87 (m, 1H), 2.20 (m, 1H), 2.07 (m, 1H), 1.63-1.75(m, 3H), 1.29-1.41 (m, 3H); LCMS (ESI) m/z 416 (M+H)⁺.

Example 199 Preparation of1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridin-7-yl)piperidin-4-ol

1-(3-((2-(((1R,2R)-2-Hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridin-7-yl)piperidin-4-ol(30 mg, 22%) was obtained as a yellow solid using a procedure analogousto that described in Step 6 of Example 117, substituting4-(2-aminopyridin-4-yl)cyclohexanol and2-chloro-3-(2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)propanalfrom Step 2 of Example 153, respectively, for 2-aminoisonicotinonitrileand 2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal used inExample 117. ¹H NMR (500 MHz, DMSO-d₆) δ 7.88 (d, J=7.4 Hz, 2H), 7.47(s, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.15 (s, 1H), 7.06 (d, J=8.4 Hz, 1H),6.76 (dd, J=2.2, 7.6 Hz, 1H), 6.63 (s, 1H), 4.74 (br s, 1H), 4.18 (s,2H), 3.63 (dd, J=4.2, 8.6 Hz, 1H), 3.54 (d, J=12.8 Hz, 2H), 3.31-3.37(m, 4H), 2.80-2.93 (m, 2H), 2.04 (d, J=11.8 Hz, 1H), 1.88-1.92 (m, 1H),1.74-1.83 (m, 2H), 1.56-1.70 (m, 2H), 1.38-1.50 (m, 2H), 1.10-1.37 (m,4H). LCMS (ESI) m/z 478 (M+H)⁺.

Example 200 Preparation of1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridin-7-yl)ethanone

Step 1: 1-(2-Aminopyridin-4-yl)ethanone was obtained as a yellow solid(398 mg, 64%) using a procedure analogous to that described in Example73, substituting 4-iodopyridin-2-amine for(1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolused in Example 73. LCMS (ESI) m/z 137 (M+H)⁺.

Step 2:1-(3-((2-(((1R,2R)-2-Hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridin-7-yl)ethanone(80 mg, 35%) was obtained as a yellow powder using a procedure analogousto that described in Step 6 of Example 117, substituting1-(2-aminopyridin-4-yl)ethanone from Step 1 of this Example and2-chloro-3-(2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)propanalfrom Step 2 of Example 153, respectively, for 2-aminoisonicotinonitrileand 2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal used inExample 117. ¹H NMR (500 MHz, DMSO-d₆) δ 8.32 (s, 1H), 8.29 (d, J=6.9Hz, 1H), 7.87 (d, J=7.4 Hz, 1H), 7.67 (s, 1H), 7.53 (s, 1H), 7.28 (br s,1H), 7.27 (d, J=7.9 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 4.72 (d, J=4.9 Hz,1H), 4.35 (s, 2H), 3.51 (br s, 1H), 2.62 (s, 3H), 2.03 (d, J=11.3 Hz,1H), 1.87 (d, J=10.8 Hz, 1H), 1.55-1.70 (m, 2H), 1.09-1.35 (m, 4H). LCMS(ESI) m/z 421 (M+H)⁺.

Example 201 Preparation of(1R,2R)-2-((6-((7-(1-hydroxyethyl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

To a stirred solution of1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridin-7-yl)ethanone(40 mg, 0.095 mmol) from Example 200 in MeOH at rt was added NaBH₄.After 30 min, 3N HCl was added and the mixture was purified byreverse-phase HPLC using a mixture of water (5% CH₃CN, 0.05% HCOOH) andCH₃CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18column as the stationary phase to afford(1R,2R)-2-((6-((7-(1-hydroxyethyl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(23 mg, 58%) as white powder. ¹H NMR (500 MHz, DMSO-d₆) δ 8.11 (d, J=7.4Hz, 1H), 7.87 (d, J=7.9 Hz, 1H), 7.50 (s, 1H), 7.41 (s, 1H), 7.37 (s,1H), 7.26 (d, J=8.4 Hz, 1H), 7.07 (d, J=7.9 Hz, 1H), 6.84 (d, J=7.4 Hz,1H), 5.30 (br s, 1H), 4.72 (q, J=6.4 Hz, 2H), 4.26 (s, 2H), 3.50 (br s,1H), 2.03 (d, J=11.8 Hz, 1H), 1.82-1.87 (m, 1H), 1.55-1.69 (m, 2H), 1.32(d, J=6.9 Hz, 3H), 1.10-1.30 (m, 4H). LCMS (ESI) m/z 423 (M+H)⁺.

Example 202 Preparation of1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridin-7-yl)ethanoneoxime

To a stirred solution of1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridin-7-yl)ethanone(40 mg, 0.095 mmol) from Example 200 in EtOH (2 mL) at rt were addedhydroxylamine hydrochloride (120 mg, excess) and pyridine (200 μL,excess). The mixture was heated at 90° C. for 1 h, and then cooled tort. Purification by reverse-phase HPLC using a mixture of water (5%CH₃CN, 0.05% HCOOH), CH₃CN (0.05% HCOOH) as the mobile phase and VarianPursuit XRs C18 column as the stationary phase afforded1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridin-7-yl)ethanoneoxime (23 mg, 61%) as yellow powder. ¹H NMR (500 MHz, DMSO-d₆) δ 11.46(br s, 1H), 8.13 (d, J=7.4 Hz, 1H), 7.90 (d, J=7.4 Hz, 1H), 7.72 (s,1H), 7.51 (s, 1H), 7.45 (s, 1H), 7.08 (d, J=8.4 Hz, 1H), 6.44-6.58 (m,1H), 5.89 (s, 1H), 4.78 (d, J=2.5 Hz, 1H), 4.29 (s, 2H), 3.50 (br s,1H), 2.18 (s, 3H), 2.04 (d, J=12.3 Hz, 1H), 1.87 (d, J=10.8 Hz, 1H),1.56-1.67 (m, 2H), 1.15-1.32 (m, 4H). LCMS (ESI) m/z 436 (M+H)⁺.

Example 203 Preparation of(1R,2R)-2-((6-((5-bromo-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: A stirred mixture of acetic anhydride (20 mL, 213 mmol) andformic acid (8 mL, 213 mmol) was heated at 60° C. for 3 h. The mixturewas cooled to rt, -bromo-2-fluoro-6-nitroaniline (2.5 g, 10.64 mmol) wasadded. The mixture was heated at 60° C. for 15 h, cooled to rt andconcentrated under reduced pressure. The residue was partitioned betweensaturated aq NaHCO₃ and DCM. The organic layer was separated, dried overMgSO₄, filtered, and concentrated under reduced pressure to affordN-(4-bromo-2-fluoro-6-nitrophenyl)formamide (2.79 g, 100%) as a brownsolid that was not purified further. LCMS (ESI) m/z 285 and 287(M+H+Na)⁺.

Step 2: To a stirred solution ofN-(4-bromo-2-fluoro-6-nitrophenyl)formamide (2.79 g, 10.61 mmol) fromthe previous step in anhydrous DMF (40 mL) at 0° C. was added sodiumhydride (60% dispersion in mineral oil, 485 mg, 12.13 mmol). The mixturewas stirred at 0° C. for 15 min, then allowed to warm to rt. To thereaction mixture was added a solution of6-(chloromethyl)-2-(methylthio)benzo[d]thiazole (3.04 g, 13.24 mmol)from Step 3 of Example 3 in DMF (10 mL), and the mixture was stirred atrt for 15 h. The mixture was partitioned between water and DCM and theorganic layer was separated and washed sequentially with water andbrine. The organic layer was separated, dried over MgSO₄, filtered, andconcentrated under reduced pressure to affordN-(4-bromo-2-fluoro-6-nitrophenyl)-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)formamide(4.8 g, 98%) as an oil, which was not purified further. LCMS (ESI) m/z456 and 458 (M+H)⁺.

Step 3: To a stirred mixture ofN-(4-bromo-2-fluoro-6-nitrophenyl)-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)formamide(4.8 g, 10.55 mmol) from the previous step, HOAc (15 mL) and EtOH (50mL) at rt was added portionwise iron powder (1.77 g, 31.65 mmol). Themixture was heated at 80° C. for 2.5 h. After cooling to rt, the mixturewas partitioned between saturated aq NaHCO₃ and a 10:1 mixture of EtOAcand MeOH. The biphasic mixture was filtered through Celite, and thelayers of the filtrate were separated. The aqueous layer was extractedwith a 10:1 mixture of EtOAc and MeOH. The combined organic layers weredried over MgSO₄, filtered, and concentrated under reduced pressure. Theresidual solid was purified by trituration with diethyl ether to afford6-((5-bromo-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole(1.39 mg, 39%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.56 (s,1H), 7.87 (m, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.75 (m, 1H), 7.30-7.34 (m,2H), 5.66 (s, 2H), 2.76 (s, 3H); LCMS (ESI) m/z 408 and 410 (M+H)⁺.

Step 4: 6-((5-Bromo-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (1.33 g, 92%) was obtained as a white solidusing a procedure analogous to that described in Step 4 of Example 130,substituting6-((5-bromo-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazolefrom Step 3 of this Example for2-(methylthio)-6-((5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazoleused in Example 130. ¹H NMR (500 MHz, DMSO-d₆) δ 8.58 (s, 1H), 8.10 (m,1H), 8.07 (d, J=10.6 Hz, 1H), 7.76 (m, 1H), 7.48 (dd, J=8.5, 1.7 Hz,1H), 7.32 (dd, J=10.6, 1.7 Hz, 1H), 5.75 (s, 2H), 3.05 (s, 3H); LCMS(ESI) m/z 424 and 426 (M+H)⁺.

Step 5: A stirred mixture of6-((5-bromo-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole(1.33 g, 3.14 mmol), (1R,2R)-2-aminocyclohexanol (1.09 g, 9.43 mmol),DIEA (1.62 g, 12.58 mmol) and DMA (40 mL) was heated in a sealed vial at110° C. for 15 h. The mixture was cooled to rt and then partitionedbetween water and EtOAc. The organic layer was separated and washedsequentially with water and brine. The organic layer was separated,dried over MgSO₄, filtered, and concentrated under reduced pressure. Theresidual solid was purified by trituration with a 6:1 mixture of diethylether and DCM to afford(1R,2R)-2-((6-((5-bromo-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(952 mg, 64%) as a tan solid. A 90 mg portion was further purified byreverse-phase preparative HPLC using a mixture of water (5% CH₃CN, 0.05%HOAc) and CH₃CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRsdiphenyl column as the stationary phase to afford(1R,2R)-2-((6-((5-bromo-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(15 mg) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.52 (s, 1H), 7.98(d, J=10.0 Hz, 1H), 7.74 (d, J=5.0 Hz, 1H), 7.54 (m, 1H), 7.33 (m, 1H),7.29 (d, J=10.0 Hz, 1H), 7.08 (m, 1H), 5.52 (s, 2H), 4.75 (d, J=5.0 Hz,1H), 3.51 (m, 1H), 3.33 (m, 1H), 2.02 (m, 1H), 1.87 (m, 1H), 1.59-1.64(m, 2H), 1.16-1.30 (m, 4H); LCMS (ESI) m/z 475 and 477 (M+H)⁺.

Example 204 Preparation of1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridin-7-yl)ethanoneO-methyl oxime

1-(3-((2-(((1R,2R)-2-Hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridin-7-yl)ethanoneO-methyl oxime was obtained as yellow powder (23 mg, 59%) using aprocedure analogous to that described in Example 202, substitutingO-methylhydroxylamine hydrochloride for hydroxylamine hydrochloride usedin Example 202. ¹H NMR (500 MHz, DMSO-d₆) δ 8.17 (d, J=7.4 Hz, 1H), 7.92(d, J=7.4 Hz, 1H), 7.79 (s, 1H), 7.51 (s, 1H), 7.46 (s, 1H), 7.27 (d,J=8.4 Hz, 2H), 7.08 (d, J=7.9 Hz, 1H), 4.78 (br s, 1H), 4.30 (s, 2H),3.94 (s, 3H), 3.50 (br s, 1H), 2.21 (s, 3H), 2.04 (d, J=11.8 Hz, 1H),1.85-1.93 (m, 1H), 1.54-1.69 (m, 2H), 1.09-1.35 (m, 4H). LCMS (ESI) m/z450 (M+H)⁺.

Example 205 Preparation of(1R,2R)-2-((6-((9H-benzo[d]imidazo[1,2-a]imidazol-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

(1R,2R)-2-((6-((9H-Benzo[d]imidazo[1,2-a]imidazol-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(17 mg, 7%) was obtained as a solid using a procedure analogous to thatdescribed in Step 3 Example 153, using2-chloro-3-(2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)propanalfrom Step 2 of Example 153 and substituting 1H-benzo[d]imidazol-2-aminefor 4-(2-methoxyethoxy)pyridin-2-amine used in Step 3 of Example 153. ¹HNMR (500 MHz, DMSO-d₆) δ 11.66 (br s, 1H), 7.87 (d, J=7.4 Hz, 1H), 7.54(s, 1H), 7.35 (dd, J=3.4, 7.9 Hz, 2H), 7.28 (d, J=8.4 Hz, 1H), 7.08-7.17(m, 2H), 6.84-6.95 (m, 2H), 4.74 (br s, 1H), 4.32 (s, 2H), 3.50 (br s,1H), 3.33 (m, 1H), 2.02 (m, 1H), 1.87 (m, 1H), 1.54-1.67 (m, 2H),1.12-1.33 (m, 4H); LCMS (ESI) m/z 418 (M+H)⁺.

Example 206 Preparation of7-fluoro-1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

A stirred mixture of(1R,2R)-2-((6-((5-bromo-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(150 mg, 0.316 mmol) from Example 203, zinc cyanide (111 mg, 0.948mmol), 1,1′-bis(diphenylphosphino)ferrocene (35 mg, 0.0632 mmol) andanhydrous DMF (2 mL) was purged with a stream of argon. To the mixturewas added palladium(trisdibenzylideneacetone) (0) (29 mg, 0.0316 mmol)and the mixture was heated in a sealed tube 100° C. for 6 h. The mixturewas cooled and additional zinc cyanide (111 mg, 0.948 mmol),1,1′-bis(diphenylphosphino)ferrocene (35 mg, 0.0632 mmol), andpalladium(trisdibenzylideneacetone) (0) (29 mg, 0.0316 mmol) were added,and heating in a sealed tube was continued at 100° C. for 15 h. Themixture was cooled to rt and purified directly by reverse-phasepreparative HPLC using a mixture of water (5% CH₃CN, 0.05% HOAc) andCH₃CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenylcolumn as the stationary phase to afford(7-fluoro-1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile(2.6 mg, 2%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.70 (s, 1H),8.13 (s, 1H), 8.02 (d, J=7.6 Hz, 1H), 7.63 (d, J=11.1 Hz, 1H), 7.57 (s,1H), 7.29 (d, J=8.1 Hz, 1H), 7.10 (d, J=8.1 Hz, 1H), 5.58 (s, 2H), 4.77(br s, 1H), 3.50 (br m, 1H), 3.30 (br m, 1H), 2.02 (m, 1H), 1.87 (m,1H), 1.55-1.67 (m, 2H), 1.12-1.32 (m, 4H); LCMS (ESI) m/z 422 (M+H)⁺.

Example 207 Preparation of(1R,2R)-2-((6-((7-fluoro-5-vinyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

A stirred mixture of(1R,2R)-2-((6-((5-bromo-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(150 mg, 0.316 mmol) from Example 203, vinyl boronic acid pinacol ester(97 mg, 0.632 mmol), sodium carbonate (67 mg, 0.0632 mmol), 1,4-dioxane(2 mL), and water (0.5 mL) was purged with a stream of argon. To themixture was added dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) DCM adduct (35 mg, 0.0474 mmol) and the mixture washeated in a sealed reaction vessel at 100° C. for 2.5 h. The mixture wascooled to rt and purified directly by reverse-phase preparative HPLCusing a mixture of water (5% CH₃CN, 0.05% HOAc) and CH₃CN (0.05% HOAc)as the mobile phase and Varian Pursuit XRs diphenyl column as thestationary phase to afford(1R,2R)-2-((6-((7-fluoro-5-vinyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(23 mg, 17%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.44 (s, 1H),7.98 (d, J=7.6 Hz, 1H), 7.55 (d, J=6.9 Hz, 2H), 7.23-7.31 (m, 2H), 7.09(m, 1H), 6.79 (dd, J=11.0, 17.6 Hz, 1H), 5.83 (d, J=17.5 Hz, 1H), 5.51(s, 2H), 5.22 (d, J=11.1 Hz, 1H), 4.74 (d, J=4.4 Hz, 1H), 3.51 (br m,1H), 3.30 (br m, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.55-1.67 (m, 2H),1.14-1.32 (m, 4H); LCMS (ESI) m/z 423 (M+H)⁺.

Example 208 Preparation of(1R,2R)-2-((6-((5-(3,6-dihydro-2H-pyran-4-yl)-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

A stirred mixture of(1R,2R)-2-((6-((5-bromo-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(150 mg, 0.316 mmol) from Example 203, 3,6-dihydro-2H-pyran-4-boronicacid pinacol ester (133 mg, 0.632 mmol), sodium carbonate (67 mg, 0.0632mmol), 1,4-dioxane (2 mL), and water (0.5 mL) was purged with a streamof argon. To the mixture was addeddichloro[1,1′-bis(diphenylphosphino)ferrocene] palladium (II) DCM adduct(35 mg, 0.0474 mmol) and the mixture was heated in a sealed vessel at100° C. for 3 h. The mixture was cooled to rt and purified directly byreverse-phase preparative HPLC using a mixture of water (5% CH₃CN, 0.05%HOAc) and CH₃CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRsdiphenyl column as the stationary phase to afford(1R,2R)-2-((6-((5-(3,6-dihydro-2H-pyran-4-yl)-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(55 mg, 36%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.43 (s, 1H),7.95 (d, J=7.6 Hz, 1H), 7.49-7.56 (m, 2H), 7.29 (d, J=8.1 Hz, 1H), 7.21(d, J=13.0 Hz, 1H), 7.09 (m, 1H), 6.27 (br m, 1H), 5.51 (s, 2H), 4.72(d, J=5.2 Hz, 1H), 4.21 (d, J=2.5 Hz, 2H), 4.06 (m, 1H), 3.81 (t, J=5.4Hz, 2H), 3.61 (m, 1H), 3.51 (br m, 1H), 3.30 (br m, 1H), 2.00 (m, 1H),1.88 (m, 1H), 1.55-1.67 (m, 2H), 1.11-1.32 (m, 4H); LCMS (ESI) m/z 479(M+H)⁺.

Example 209 Preparation of(1R,2R)-2-((6-((5-morpholino-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

(1R,2R)-2-((6-((5-Morpholino-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(10 mg, 7%) was obtained as a solid using a procedure analogous to thatdescribed in Example 97, substituting(1R,2R)-2-((6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolfrom Step 5 of Example 183 for(1R,2R)-2-((6-((6-iodo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolfrom Example 97. ¹H NMR (500 MHz, DMSO-d₆) δ 8.42 (br s, 1H), 7.62 (brs, 1H), 7.57 (s, 1H), 7.47 (br s, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.15 (d,J=7.9 Hz, 2H), 6.94 (d, J=8.9 Hz, 1H), 5.40 (s, 2H), 4.42 (br s, 1H),3.70-3.81 (m, 4H), 3.52 (m, 1H), 3.41 (br s, 1H), 3.06-3.11 (m, 4H),2.07 (m, 1H), 1.90 (m, 1H), 1.60-1.70 (m, 2H), 1.20-1.36 (m, 4H); LCMS(ESI) m/z 464 (M+H)⁺.

Example 210 Preparation of1-(1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)piperidin-2-one

To a stirred mixture of copper iodide (23 mg, 0.12 mmol) andtripotassium phosphate (190 mg, 0.90 mmol) in DMSO (3 mL) were added(1R,2R)-2-((6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(150 mg, 0.30 mmol) from Step 5 of Example 183 and piperidin-2-one (200mg, 2.02 mmol). The mixture was flushed with argon and heated in asealed reaction vessel at 125° C. for 15 h. The reaction mixture wascooled to rt and filtered, and the filtrate was purified directly byreverse-phase preparative HPLC using a mixture of water (5% CH₃CN, 0.05%HOAc) and CH₃CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRsdiphenyl column as the stationary phase to afford1-(1-((2-(((1R,2R)-2-Hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)piperidin-2-one(3 mg, 7%) as a solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.31 (br s, 1H), 7.69(br s, 1H), 7.62 (s, 1H), 7.44-7.53 (m, 2H), 7.30 (d, J=8.4 Hz, 1H),7.18 (d, J=8.4 Hz, 1H), 7.08 (d, J=8.9 Hz, 1H), 5.45 (s, 2H), 3.62 (t,J=5.4 Hz, 2H), 3.51 (br s, 1H), 3.37-3.46 (m, 2H), 2.36-2.43 (m, 2H),2.06 (m, 1H), 1.82-1.93 (m, 5H), 1.61-1.70 (m, 2H), 1.20-1.36 (m, 4H);LCMS (ESI) m/z 476 (M+H)⁺.

Example 211 Preparation of(1R,2R)-2-((6-((5-(1H-pyrazol-3-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

To a stirred solution of(1R,2R)-2-((6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(100 mg, 0.20 mmol) from Step 5 of Example 183 in DMF (2 mL) were added(1H-pyrazol-3-yl)boronic acid (90 mg, 0.80 mmol), NaHCO₃ (100 mg 1.2mmol), bis(triphenylphosphine) palladium(II) dichloride (28 mg, 0.04mmol), and water (0.4 mL). The mixture was flushed with argon and heatedin a sealed vessel at 90° C. for 15 h. The reaction mixture was cooledto rt and partitioned between DCM and water. The aqueous layer wasextracted twice with DCM and the combined organic phases were washedthree times with a 1:1 mixture of water and brine. The organic phaseswere then dried over MgSO₄, filtered, and concentrated under reducedpressure. The residue was purified by silica gel flash chromatographyeluting with 100% DCM to 10% MeOH/DCM to afford(1R,2R)-2-((6-((5-(1H-pyrazol-3-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(4 mg, 5%) as a solid. ¹H NMR (500 MHz, DMSO-d₆) δ 12.92 (br s, 1H),12.53 (br s, 1H), 8.29 (br s, 1H), 8.03 (m, 1H), 7.58-7.74 (m, 3H), 7.53(d, J=7.9 Hz, 1H), 7.31 (d, J=7.9 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 6.63(br s, 1H), 5.47 (s, 2H), 4.42 (d, J=4.4 Hz, 1H), 3.51 (br s, 1H), 3.41(tt, J=4.5, 8.8 Hz, 1H), 2.06 (m, 1H), 1.90 (d, J=11.8 Hz, 1H),1.57-1.71 (m, 2H), 1.19-1.36 (m, 4H); LCMS (ESI) m/z 445 (M+H)⁺.

Example 212 Preparation of(1R,2R)-2-((6-((6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: A mixture of 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (500mg, 2.21 mmol), (2-(methylthio)benzo[d]thiazol-6-yl)methanamine fromStep 4 of Example 23 (583 mg, 2.76 mmol), and triethylamine (837 mg,8.29 mmol) in DMF (10 mL) was stirred at rt overnight. The reactionmixture was diluted with EtOAc and washed with water. The organic layerwas dried over Na₂SO₄, filtered and concentrated under reduced pressure.The residue was purified by silica gel chromatography eluting with 1:0to 10:1 petroleum ether/EtOAc to giveN-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3-nitro-5-(trifluoromethyl)pyridin-2-amineas a yellow solid (150 mg, 84.7%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.46 (t,J=1.8 Hz, 1H), 8.78 (d, J=2.1 Hz, 1H), 8.66 (d, J=2.4 Hz, 1H), 7.97 (s,1H), 7.78 (d, J=8.4 Hz, 1H), 7.49-7.45 (m, 1H), 4.95 (d, J=6.6 Hz, 2H),2.77 (s, 3H); LCMS (ESI) m/z 401 (M+H)⁺.

Step 2: To a mixture ofN-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3-nitro-5-(trifluoromethyl)pyridin-2-amine(0.97 g, 2.42 mmol), HOAc (4 mL), and MeOH (4 mL) in DCM (30 mL) cooledin ice-water bath was slowly added zinc dust (1.6 g, 24.2 mmol). Thereaction mixture was stirred at 0° C. for 2 h. The mixture was filteredand the filtrate was diluted with DCM and then washed with water and aqNaHCO₃. The organic layer was dried over Na₂SO₄, filtered andconcentrated under reduced pressure to affordN²-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-5-(trifluoromethyl)pyridine-2,3-diamine(0.89 g, 100%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.05 (s, 1H), 7.82 (d, J=8.4Hz, 1H), 7.77 (s, 1H), 7.44-7.41 (m, 1H), 7.03 (d, J=1.8 Hz, 1H), 4.84(br s, 1H), 4.78 (d, J=5.1 Hz, 2H), 3.29 (br s, 2H), 2.79 (s, 3H). LCMS(ESI) m/z 371 (M+H)⁺.

Step 3: A mixture ofN²-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-5-(trifluoromethyl)pyridine-2,3-diamine(0.89 g, 2.39 mmol), triethoxymethane (30 mL) and HCOOH (0.6 g) wasstirred at 90° C. for 2 h. The mixture was concentrated under reducedpressure. The residue was purified by silica gel chromatography elutingwith 2:1 to 0:1 petroleum ether/EtOAc to afford2-(methylthio)-6-((6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazoleas a light yellow solid (0.77 g, 79.3%). ¹H NMR (300 MHz, DMSO-d₆) δ8.88 (s, 1H), 8.77 (d, J=1.2 Hz, 1H), 8.57 (d, J=1.8 Hz, 1H), 8.00 (d,J=1.2 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.49-7.46 (m, 1H), 5.68 (s, 2H),2.77 (s, 3H). LCMS (ESI) m/z 381 (M+H)⁺.

Step 4: A mixture of2-(methylthio)-6-((6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazole(200 mg, 0.53 mmol) and m-CPBA (114 mg, 0.66 mmol) in DCM (5 mL) wasstirred in an ice-water bath for 2 h. The mixture was diluted with DCMand washed with aq Na₂S₂O₃, aq NaHCO₃ and water. The organic layer wasdried over Na₂SO₄, filtered and concentrated under reduced pressure toafford2-(methylsulfinyl)-6-((6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazoleas a yellow solid (180 mg, 87.8%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.91 (s,1H), 8.77 (s, 1H), 8.59 (s, 1H), 8.23 (s, 1H), 8.08 (d, J=8.1 Hz, 1H),7.66-7.62 (m, 1H), 5.77 (s, 2H), 3.06 (s, 3H). LCMS (ESI) m/z 397(M+H)⁺.

Step 5: A mixture of2-(methylsulfinyl)-6-((6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazole(180 mg, 0.45 mmol), (1R,2R)-2-aminocyclohexanol (112 mg, 0.97 mmol) andDIEA (261 mg, 2 mmol) in DMA (2 mL) was stirred at 130° C. overnight.The reaction mixture was diluted with EtOAc and washed with brine. Theorganic layer was dried over NaSO₄, filtered and concentrated underreduced pressure. The residue was purified by preparative HPLC to afford(1R,2R)-2-((6-((6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolas a yellow solid (64 mg, 31.8%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.84 (s,1H), 8.78 (d, J=1.2 Hz, 1H), 8.55 (d, J=1.5 Hz, 1H), 7.95 (d, J=7.8 Hz,1H), 7.68 (d, J=1.5 Hz, 1H), 7.29 (d, J=7.8 Hz, 1H), 7.25-7.22 (m, 1H),5.55 (s, 2H), 4.71 (d, J=5.1 Hz, 1H), 3.52-3.50 (m, 1H), 3.37-3.33 (m,1H), 2.08-2.01 (m, 1H), 1.87-1.85 (m, 1H), 1.64-1.60 (m, 2H), 1.29-1.19(m, 4H). LCMS (ESI) m/z 448 (M+H)⁺.

Example 213 Preparation of(1S,2S)-2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

(1S,2S)-2-((6-((6-Fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolwas synthesized as a white powder (48 mg, 42%) using a procedureanalogous to that described in Step 5 of Example 162, substituting(1S,2S)-2-aminocyclohexanol for (1S,2R)-2-aminocyclohexanolhydrochloride used in Example 162. ¹H NMR (500 MHz, DMSO-d₆) δ 8.67 (s,1H), 8.41 (t, J=2.0 Hz, 1H), 8.07 (dd, J=2.6, 9.5 Hz, 1H), 7.95 (d,J=7.6 Hz, 1H), 7.66 (d, J=1.2 Hz, 1H), 7.28 (m, 1H), 7.22 (dd, J=1.5,8.4 Hz, 1H), 5.48 (s, 2H), 4.72 (d, J=5.2 Hz, 1H), 3.51 (m, 1H), 3.33(m, 1H), 2.02 (m, 1H), 1.87 (m, 1H), 1.57-1.65 (m, 2H), 1.15-1.29 (m,4H); LCMS (ESI) m/z 399 (M+H)⁺.

Example 214 Preparation of(1R,2R)-2-((6-((7-(1H-imidazol-1-yl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

(1R,2R)-2-((6-((7-(1H-Imidazol-1-yl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(27 mg, 47%) was obtained as a light tan solid using a procedureanalogous to that described in Example 141, substituting(1R,2R)-2-((6-((7-iodoimidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolfrom Step 1 of Example 167 and imidazole, respectively, for(1R,2R)-2-((6-((6-iodo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanoland pyrazole used in Example 141. ¹H NMR (500 MHz, DMSO-d₆) δ 8.42 (brs, 1H), 8.34 (d, J=6.9 Hz, 1H), 7.93 (br s, 1H), 7.90 (d, J=7.4 Hz, 2H),7.54 (s, 1H), 7.49 (br s, 1H), 7.33 (d, J=7.4 Hz, 1H), 7.27 (d, J=8.4Hz, 1H), 7.01-7.19 (m, 2H), 4.77 (br s, 1H), 4.33 (s, 2H), 3.51 (br s,1H), 3.31-3.34 (m, 2H), 2.04 (d, J=11.8 Hz, 1H), 1.87 (d, J=10.8 Hz,1H), 1.53-1.70 (m, 2H), 1.06-1.36 (m, 4H). LCMS (ESI) m/z 445 (M+H)⁺.

Example 215 Preparation of(1R,2R)-2-((6-((7-(2H-1,2,3-triazol-2-yl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

(1R,2R)-2-((6-((7-(2H-1,2,3-Triazol-2-yl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(13 mg, 23%) was obtained as a light tan solid using a procedureanalogous to that described in Example 141, substituting(1R,2R)-2-((6-((7-iodoimidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolfrom Step 1 of Example 167 and 1,2,3-triazole, respectively, for(1R,2R)-2-((6-((6-iodo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanoland pyrazole used in Example 141. ¹H NMR (500 MHz, DMSO-d₆) δ 8.40 (d,J=7.4 Hz, 1H), 8.18 (s, 2H), 8.04 (s, 1H), 7.90 (d, J=7.9 Hz, 1H), 7.63(dd, J=2.0, 7.4 Hz, 1H), 7.54 (s, 1H), 7.51 (s, 1H), 7.28 (d, J=8.4 Hz,1H), 7.11 (d, J=6.9 Hz, 1H), 4.77 (br s, 1H), 4.34 (s, 2H), 3.51 (br s,3H), 2.04 (d, J=11.8 Hz, 1H), 1.87 (d, J=11.3 Hz, 1H), 1.55-1.69 (m,2H), 1.10-1.36 (m, 4H). LCMS (ESI) m/z 446 (M+H)⁺.

Example 216 Preparation of(1R,2R)-2-((6-((7-vinylimidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: Crude 4-vinylpyridin-2-amine (200 mg) was obtained as a lighttan solid using a procedure analogous to that described in Example 98,substituting 4-iodopyridin-2-amine for(1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolused in Example 98. LCMS (ESI) m/z 121 (M+H)⁺.

Step 2:(1R,2R)-2-((6-((7-Vinylimidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(13 mg, 8%) was obtained as a light tan solid using a procedureanalogous to that described in Step 6 of Example 117, substituting4-vinylpyridin-2-amine from Step 1 of this Example and2-chloro-3-(2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)propanalfrom Step 2 of Example 153, respectively, for 2-aminoisonicotinonitrileand 2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal used inExample 117. ¹H NMR (500 MHz, DMSO-d₆) δ 8.14 (d, J=6.9 Hz, 1H), 7.86(d, J=7.4 Hz, 1H), 7.52 (d, J=3.4 Hz, 2H), 7.40 (s, 1H), 7.26 (d, J=7.9Hz, 1H), 7.13 (d, J=5.9 Hz, 1H), 7.09 (d, J=6.9 Hz, 1H), 6.77 (dd,J=10.8, 17.7 Hz, 1H), 5.91 (d, J=17.7 Hz, 1H), 5.34 (d, J=11.3 Hz, 1H),4.72 (d, J=3.4 Hz, 1H), 4.28 (s, 2H), 3.52 (d, J=8.4 Hz, 2H), 2.03 (d,J=10.8 Hz, 1H), 1.87 (d, J=11.3 Hz, 1H), 1.54-1.70 (m, 2H), 1.11-1.36(m, 4H). LCMS (ESI) m/z 405 (M+H)⁺.

Example 217 Preparation of(1R,2R)-2-((6-((7-(allyloxy)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: To a stirred solution of 2-aminopyridin-4-ol (500 mg, 4.5 mmol)in DMF (5 mL) at rt was added K₂CO₃ (940 mg, 6.8 mmol). The resultingmixture was stirred at rt for 20 min before allyl bromide (393 μL, 4.5mmol) was added. The mixture was then stirred at rt overnight and heatedat 60° C. for 2 h. After cooling to rt, the mixture was partitionedbetween EtOAc and water, and the organic layer was washed with brine,dried over Na₂SO₄, and evaporated under reduced pressure. The residuewas purified by silica gel chromatography eluting with EtOAc in hexanesto give 4-(allyloxy)pyridin-2-amine (110 mg, 16%) as a white solid. LCMS(ESI) m/z 151 (M+H)⁺.

Step 2:(1R,2R)-2-((6-((7-(Allyloxy)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(56 mg, 34%) was obtained as a light tan solid using a procedureanalogous to that described in Step 6 of Example 117, substituting4-(allyloxy)pyridin-2-amine from Step 1 of this Example and2-chloro-3-(2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)propanalfrom Step 2 of Example 153, respectively, for 2-aminoisonicotinonitrileand 2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal used inExample 117. ¹H NMR (500 MHz, DMSO-d₆) δ 8.02 (d, J=7.4 Hz, 1H), 7.88(d, J=7.9 Hz, 1H), 7.49 (s, 1H), 7.26 (d, J=7.9 Hz, 1H), 7.23 (s, 1H),7.07 (d, J=8.4 Hz, 1H), 6.92 (d, J=2.5 Hz, 1H), 6.60 (dd, J=2.5, 7.4 Hz,1H), 5.96-6.10 (m, 1H), 5.42 (d, J=17.2 Hz, 1H), 5.28 (d, J=10.3 Hz,1H), 4.75 (br s, 1H), 4.61 (d, J=5.4 Hz, 2H), 4.22 (s, 2H), 3.51 (br s,2H), 2.04 (d, J=11.8 Hz, 1H), 1.87-1.94 (m, 1H), 1.55-1.69 (m, 2H),1.11-1.36 (m, 4H). LCMS (ESI) m/z 435 (M+H)⁺.

Example 218 Preparation of(1R,2R)-2-((6-((7-(1H-1,2,3-triazol-1-yl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

(1R,2R)-2-((6-((7-(1H-1,2,3-triazol-1-yl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(6 mg, 11%) was obtained as a light tan solid using a procedureanalogous to that described in Example 141, substituting(1R,2R)-2-((6-((7-iodoimidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolfrom Step 1 of Example 167 and 1,2,3-triazole, respectively, for(1R,2R)-2-((6-((6-iodo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanoland pyrazole used in Example 141. ¹H NMR (500 MHz, DMSO-d₆) δ 8.98 (s,1H), 8.44 (d, J=7.4 Hz, 1H), 8.17 (s, 1H), 8.01 (s, 1H), 7.96 (d, J=7.4Hz, 1H), 7.58 (d, J=7.4 Hz, 1H), 7.55 (br s, 2H), 7.28 (d, J=8.4 Hz,1H), 7.11 (d, J=8.4 Hz, 1H), 4.83 (br s, 1H), 4.35 (s, 2H), 3.50 (br s,3H), 2.04 (d, J=11.8 Hz, 1H), 1.87 (d, J=10.8 Hz, 1H), 1.54-1.67 (m,2H), 1.08-1.33 (m, 4H). LCMS (ESI) m/z 446 (M+H)⁺.

Example 219 Preparation ofN-((1R,2S)-2-chlorocyclohexyl)-6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-amine

N-((1R,2S)-2-Chlorocyclohexyl)-6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-aminewas synthesized as a white powder (6 mg, 2%) using a procedure analogousto that described in Example 198, substituting(1R,2R)-2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolfor(1S,2R)-2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolused in Example 198. ¹H NMR (500 MHz, CDCl₃) δ 8.68 (s, 1H), 8.41 (s,1H), 8.24 (d, J=8.4 Hz, 1H), 8.07 (dd, J=2.6, 9.5 Hz, 1H), 7.68 (s, 1H),7.33 (d, J=8.4 Hz, 1H), 7.24 (dd, J=1.4, 8.2 Hz, 1H), 5.48 (s, 2H), 4.02(m, 1H), 3.87 (m, 1H), 2.20 (m, 1H), 2.07 (m, 1H), 1.63-1.75 (m, 3H),1.29-1.41 (m, 3H); LCMS (ESI) m/z 416 (M+H)⁺.

Example 220 Preparation of3-amino-1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)pyrazin-2(1H)-oneacetate salt

Step 1: To a stirred mixture of sodium iodide (4.89 g, 32.67 mmol) and2-iodo-3-methoxypyrazine (2.57 g, 10.89 mmol) in acetonitrile (30 mL) atrt was added trimethylsilyl chloride (3.55 g, 32.67 mmol). The mixturewas heated at 70° C. for 1.5 h. The mixture was cooled to rt andpartitioned between a mixture of DCM, MeOH, and aq 2 M HCl. The organiclayer was separated and the aqueous layer was extracted with additionalDCM/MeOH mixture. The combined organic layers were dried over MgSO₄,filtered, and concentrated under reduced pressure to afford3-iodopyrazin-2(1H)-one (1.21 g, 50%) as a brown solid that did notrequire further purification. ¹H NMR (500 MHz, DMSO-d₆) δ 12.54 (br s,1H), 7.42 (d, J=3.7 Hz, 1H), 7.17 (d, J=3.7 Hz, 1H); LCMS (ESI) m/z 223(M+H)⁺.

Step 2:3-Iodo-1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyrazin-2(1H)-one(1 g) was obtained as a brown solid using a procedure analogous to thatdescribed in Step 2 of Example 203, substituting 3-iodopyrazin-2(1H)-onefrom Step 1 of this Example forN-(4-bromo-2-fluoro-6-nitrophenyl)formamide used in Example 203. ¹H NMR(500 MHz, DMSO-d₆) δ 7.98 (s, 1H), 7.81-7.85 (m, 2H), 7.45 (m, 1H), 7.23(m, 1H), 5.19 (s, 2H), 2.77 (s, 3H); LCMS (ESI) m/z 416 (M+H)⁺.

Step 3: A stirred mixture of3-iodo-1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyrazin-2(1H)-one(750 mg, 1.81 mmol), ammonia (7 M solution in MeOH, 2 mL, 14 mmol), andDMSO (1.5 mL), was heated in a Biotage Microwave Synthesizer at 150° C.for 15 min. The mixture was cooled to and partitioned between EtOAc anda 1:1 mixture of water and brine. The organic layer was separated, driedover MgSO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by silica gel flash chromatography eluting with agradient of 100% DCM to 2% MeOH in DCM to afford3-amino-1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyrazin-2(1H)-one(149 mg) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆) δ 7.96 (s, 1H),7.82 (d, J=8.4 Hz, 1H), 7.43 (dd, J=1.5, 8.4 Hz, 1H), 6.92 (d, J=4.7 Hz,1H), 6.65-6.67 (br m, 3H), 5.11 (s, 2H), 2.78 (s, 3H); LCMS (ESI) m/z305 (M+H)⁺.

Step 4:3-Amino-1-((2-(methylsulfinyl)benzo[d]thiazol-6-yl)methyl)pyrazin-2(1H)-one(84 mg, 54%) was obtained as a yellow solid using a procedure analogousto that described in Step 4 of Example 130, substituting3-amino-1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyrazin-2(1H)-onefrom Step 3 of this Example for2-(methylthio)-6-((5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazoleused in Example 130. ¹H NMR (500 MHz, DMSO-d₆) δ 8.20 (s, 1H), 8.08 (d,J=8.6 Hz, 1H), 7.59 (dd, J=1.5, 8.4 Hz, 1H), 6.94 (d, J=4.7 Hz, 1H),6.69 (d, J=4.4 Hz, 3H), 5.19 (s, 2H), 3.07 (s, 3H); LCMS (ESI) m/z 321(M+H)⁺.

Step 5:3-Amino-1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)pyrazin-2(1H)-oneacetate salt (19 mg, 17%) was obtained as a solid using a procedureanalogous to that described in Step 5 of Example 203, substituting3-amino-1-((2-(methylsulfinyl)benzo[d]thiazol-6-yl)methyl)pyrazin-2(1H)-onefrom Step 4 of this Example for6-((5-bromo-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazoleused in Example 130. ¹H NMR (500 MHz, DMSO-d₆) δ 7.99 (d, J=7.4 Hz, 1H),7.62 (s, 1H), 7.30 (d, J=8.1 Hz, 1H), 7.19 (dd, J=1.5, 8.1 Hz, 1H), 6.87(d, J=4.7 Hz, 1H), 6.60-6.80 (m, 3H), 4.99 (s, 2H), 3.20-3.60 (m, 4H),2.04 (m, 1H), 1.88 (s, 3H), 1.57-1.67 (m, 2H), 1.12-1.33 (m, 4H); LCMS(ESI) m/z 372 (M+H)⁺.

Example 221 Preparation of3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-b]pyridazine-6-carbonitrile

Step 1: A stirred mixture of2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal from Step 4 ofExample 117 (1.3 g, 4.8 mmol) and 6-aminopyridazine-3-carbonitrile (0.8g, 7.2 mmol) in 1-butanol (48 mL) was heated at reflux overnight. Themixture was cooled to rt and water (100 mL) was added. The mixture wasextracted with EtOAc (3×60 mL, and the combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by silica gel chromatographyeluting with 50:1 to 20:1 DCM/MeOH to afford3-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-b]pyridazine-6-carbonitrileas a yellow solid (0.7 g, 44%). ¹H NMR (300 MHz, CDCl₃) δ 8.09 (d, J=9.0Hz, 1H), 7.83-7.78 (m, 2H), 7.69 (s, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.29(d, J=9.3 Hz, 1H), 4.46 (s, 2H), 2.78 (s, 3H). LCMS (ESI) m/z 338(M+H)⁺.

Step 2: To a solution of3-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-b]pyridazine-6-carbonitrile(0.7 g, 2.1 mmol) in DCM (30 mL) at 0° C. was slowly added m-CPBA (0.4g, 2.1 mmol). The reaction mixture was stirred at 0° C. for 2 h, then aqNa₂SO₃ (25 mL) was added and the mixture was stirred for 0.5 h. Theorganic layer was separated and dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography eluting with 50:1 to 20:1 DCM/MeOH to afford3-((2-(methylsulfinyl)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-b]pyridazine-6-carbonitrileas a yellow solid (0.7 g, 96%). ¹H NMR (300 MHz, CDCl₃) δ 8.11 (d, J=9.3Hz, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.92 (s, 1H), 7.82 (s, 1H), 7.51 (d,J=8.4 Hz, 1H), 7.31 (d, J=9.3 Hz, 1H), 4.54 (s, 2H), 3.07 (s, 3H). LCMS(ESI) m/z 354 (M+H)⁺.

Step 3: A mixture of3-((2-(methylsulfinyl)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-b]pyridazine-6-carbonitrile(300 mg, 0.9 mmol), (1R,2R)-2-aminocyclohexanol (293 mg, 2.5 mmol) andDIEA (219 mg, 1.7 mmol) in NMP (16 mL) was stirred at 135° C. overnight.The mixture was cooled to rt and water (40 mL) was added. The mixturewas extracted with EtOAc (3×30 mL). The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by silica gel chromatographyeluting with 50:1 to 20:1 DCM/MeOH to afford3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-b]pyridazine-6-carbonitrileas a brown solid (100 mg, 30%). 1H NMR (300 MHz, DMSO-d₆) δ 8.40 (d,J=9.3 Hz, 1H), 7.87-7.84 (m, 2H), 7.70 (d, J=9.3 Hz, 1H), 7.55 (d, J=1.5Hz, 1H), 7.28 (d, J=8.1 Hz, 1H), 7.13 (dd, J=1.5, 8.1 Hz, 1H), 4.72 (d,J=5.1 Hz, 1H), 4.36 (s, 2H), 3.54-3.51 (m, 1H), 3.39-3.36 (m, 1H),2.06-2.02 (m, 1H), 1.90-1.86 (m, 1H), 1.65-1.59 (m, 2H), 1.31-1.17 (m,4H). LCMS (ESI) m/z 405 (M+H)⁺.

Example 222 Preparation of1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3-morpholinopyrazin-2(1H)-one

Step 1: A mixture of 2,3-dichloropyrazine (894 mg, 6 mmol), morpholine(523 mg, 6 mmol) and DIEA (1.55 g, 12 mmol) in DMSO (8 mL) was stirredat 70° C. for 2 h. The reaction mixture was poured into water (30 mL)and extracted with ethyl acetate (3×20 mL). The combined organic layerswere washed with 2N aq HCl (30 mL), water (2×30 mL) and brine, driedover Na₂SO₄, filtered and concentrated under reduced pressure to give4-(3-chloropyrazin-2-yl)morpholine as a light yellow solid (1.01 g,92.8%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.11 (d, J=2.4 Hz, 1H), 7.90 (d,J=2.7 Hz, 1H), 3.86 (t, J=9.3 Hz, 4H), 3.45 (t, J=9.6 Hz, 4H). LCMS(ESI) m/z 200 (M+H)⁺.

Step 2: A mixture of 4-(3-chloropyrazin-2-yl)morpholine (894 mg, 6 mmol)and aq NaOH (13 mL, 52 mmol) in DMSO (18 mL) was stirred at 80° C. for 2h. The reaction mixture was poured into water (30 mL) and extracted withethyl acetate (3×20 mL). The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated under reducedpressure to give 3-morpholinopyrazin-2(1H)-one as a light yellow solid(807 mg, 92.9%). ¹H NMR (300 MHz, CDCl₃) δ 11.80 (br s, 1H), 7.05 (d,J=4.2 Hz, 1H), 6.73 (d, J=4.2 Hz, 1H), 3.84 (s, 8H). LCMS (ESI) m/z 182(M+H)⁺.

Step 3: To a stirred solution of 3-morpholinopyrazin-2(1H)-one (317 mg,1.75 mmol) in DMF (8 mL) at 0° C. was added NaH (60% in mineral oil, 105mg, 2.63 mmol). After stirring for 20 min, a solution of6-(chloromethyl)-2-(methylthio)benzo[d]thiazole (400 mg, 1.75 mmol) inDMF (2 mL) was added dropwise, and the mixture was stirred at rt for 2h. The mixture was poured into water and extracted with ethyl acetate(3×20 mL). The combined organic layers were washed with brine, driedover Na₂SO₄, filtered and concentrated under reduced pressure to give1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3-morpholinopyrazin-2(1H)-oneas a light yellow solid (625 mg, 95.4%). ¹H NMR (300 MHz, CDCl₃) δ 7.82(d, J=8.4 Hz, 1H), 7.71 (s, 1H), 7.36 (d, J=6.6 Hz, 1H), 6.92 (d, J=4.2Hz, 1H), 6.71 (d, J=4.2 Hz, 1H), 5.10 (s, 2H), 3.81 (s, 8H), 2.80 (s,3H). LCMS (ESI) m/z 375 (M+H)⁺.

Step 4: A solution of1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3-morpholinopyrazin-2(1H)-one(752 mg, 2.0 mmol) and m-CPBA (449 mg, 2.6 mmol) in DCM (20 mL) wasstirred at 0° C. for 4 h. The reaction mixture was washed with aqueousNa₂S₂O₃ and brine. The organic layer was dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography eluting with 1:3 petroleum ether/ethyl acetate togive 1-((2-(methylsulfinyl)benzo[d]thiazol-6-yl)methyl)-3-morpholinopyrazin-2(1H)-one as alight yellow solid (430 mg, 55.1%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.20 (s,1H), 8.08 (d, J=8.4 Hz, 1H), 7.59 (d, J=6.9 Hz, 1H), 7.29 (d, J=4.5 Hz,1H), 6.96 (d, J=4.2 Hz, 1H), 5.20 (s, 2H), 3.65 (s, 8H), 3.07 (s, 3H).LCMS (ESI) m/z 391 (M+H)⁺.

Step 5: A mixture of1-((2-(methylsulfinyl)benzo[d]thiazol-6-yl)methyl)-3-morpholinopyrazin-2(1H)-one (250 mg, 0.64 mmol), (1R,2R)-2-aminocyclohexanol (221mg, 1.92 mmol) and DIEA (248 mg, 1.92 mmol) in DMA (6.6 mL) was stirredat 130° C. for 16 h. The reaction mixture was cooled to rt and pouredinto water (30 mL). The mixture extracted with ethyl acetate (3×100 mL)and the combined organic layers were washed with brine, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by silica gel chromatography eluting with 1:5 petroleumether/ethyl acetate to give1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3-morpholinopyrazin-2(1H)-oneas a light yellow solid (120 mg, 26.5%). ¹H NMR (300 MHz, DMSO-d₆) δ7.96 (d, J=7.2 Hz, 1H), 7.63 (s, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.18-7.22(m, 2H), 6.90 (d, J=4.8 Hz, 1H), 5.01 (s, 2H), 4.72 (d, J=5.1 Hz, 1H),3.65 (s, 8H), 3.55-3.52 (m, 1H), 3.36-3.31 (m, 1H), 2.07-2.02 (m, 1H),1.90-1.86 (m, 1H), 1.63-1.62 (m, 2H), 1.30-1.22 (m, 4H). LCMS (ESI) m/z442 (M+H)⁺.

Example 223 Preparation of(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridin-7-yl)(pyrrolidin-1-yl)methanone

(3-((2-(((1R,2R)-2-Hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridin-7-yl)(pyrrolidin-1-yl)methanone(65 mg, 46%) was obtained as a light tan solid using a procedureanalogous to that described in Step 6 of Example 117, substituting(2-aminopyridin-4-yl)(pyrrolidin-1-yl)methanone and2-chloro-3-(2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)propanalfrom Step 2 of Example 153, respectively, for 2-aminoisonicotinonitrileand 2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal used inExample 117. ¹H NMR (500 MHz, DMSO-d₆) δ 8.24 (d, J=6.9 Hz, 1H), 8.01(d, J=7.4 Hz, 1H), 7.72 (s, 1H), 7.53 (s, 2H), 7.31 (br s, 1H), 7.27 (d,J=7.9 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 6.99 (d, J=6.9 Hz, 1H), 6.78 (brs, 1H), 4.88 (br s, 1H), 4.31 (s, 2H), 3.43-3.58 (m, 6H), 2.04 (d,J=12.3 Hz, 1H), 1.76-1.94 (m, 5H), 1.57-1.68 (m, 2H), 1.10-1.27 (m, 4H).LCMS (ESI) m/z 476 (M+H)⁺.

Example 224 Preparation of(E)-3-(1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)acrylicacid

Step 1: To a stirred solution of(1R,2R)-2-((6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(150 mg, 0.30 mmol) from Step 5 of Example 183 in DMF (2 mL) were addedethyl acrylate (0.036 mL, 0.33 mmol), palladium (II) acetate (7 mg 0.03mmol), and triethylamine (0.088 mL, 0.63 mmol). The mixture was flushedwith argon and heated in a sealed vessel at 120° C. for 3 h. The mixturewas cooled to rt and partitioned between EtOAc and water. The separatedaqueous layer was extracted twice with EtOAc and the combined organicphases were washed three times with a 1:1 mixture of water and brine,dried over MgSO₄, filtered, and concentrated under reduced pressure toafford (E)-ethyl3-(1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)acrylate(187 mg) as a solid. The product was used directly in the next step.LCMS (ESI) m/z 477 (M+H)⁺.

Step 2: To a stirred solution of (E)-ethyl3-(1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)acrylatefrom the previous step in THF (2 mL) was added 1M aq LiOH (2 mL) and themixture was stirred at rt for 48 h. The mixture was then acidified andconcentrated under reduced pressure. The residue was purified directlyby reverse-phase preparative HPLC using a mixture of water (5% CH₃CN,0.05% HOAc) and CH₃CN (0.05% HOAc) as the mobile phase and VarianPursuit XRs diphenyl column as the stationary phase to afford(E)-3-(1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)acrylicacid as a solid (22 mg, 16%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.46 (s, 1H),7.90-8.01 (m, 2H), 7.68 (d, J=15.8 Hz, 1H), 7.66 (d, J=1.0 Hz, 1H), 7.58(s, 2H), 7.29 (d, J=10 Hz, 1H), 7.20 (dd, J=1.2, 8.1 Hz, 1H), 6.48 (d,J=15.8 Hz, 1H), 5.48 (s, 2H), 4.73 (br s, 1H), 3.47-3.57 (br m, 2H),2.02 (m, 1H), 1.86 (m, 1H), 1.55-1.67 (m, 2H), 1.12-1.32 (m, 4H). LCMS(ESI) m/z 449 (M+H)⁺.

Example 225 Preparation of(1R,2R)-2-((6-((5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Step 1: To a stirred solution of(1R,2R)-2-((6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(100 mg, 0.20 mmol) from Step 5 of Example 183 in DMF (2 mL) were addedN-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (93 mg,0.30 mmol), potassium carbonate (55 mg 0.40 mmol),bis-triphenylphosphine palladium (II) chloride (6.3 mg, 0.009 mmol), and1,1′-bis(diphenylphosphino)ferrocene (5 mg, 0.009 mmol). The mixture wasflushed with argon and heated in a sealed vessel at 80° C. for 15 h. Thereaction mixture was purified directly by reverse-phase preparative HPLCusing a mixture of water (5% CH₃CN, 0.05% HOAc) and CH₃CN (0.05% HOAc)as the mobile phase and Varian Pursuit XRs diphenyl column as thestationary phase to afford tert-butyl4-(1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate as a solid (35 mg, 31%). ¹H NMR (500 MHz, DMSO-d₆) δ8.38 (s, 1H), 7.97 (d, J=7.9 Hz, 1H), 7.66 (s, 1H), 7.63 (s, 1H), 7.49(d, J=8.4 Hz, 1H), 7.33 (m, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.18 (dd,J=1.2, 8.1 Hz, 1H), 6.09 (br s, 1H), 5.45 (s, 2H), 4.75 (d, J=3.9 Hz,1H), 3.98 (br s, 2H), 3.46-3.59 (m, 4H), 3.36-3.42 (m, 2H), 2.02 (m,1H), 1.87 (m, 1H), 1.56-1.67 (m, 2H), 1.38-1.48 (m, 9H), 1.13-1.32 (m,4H); LCMS (ESI) m/z 560 (M+H)⁺.

Step 2: To a stirred solution of tert-butyl4-(1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate(30 mg, 0.05 mmol) from the previous step in DCM (3 mL) at 0° C. wasadded 4M HCl in 1,4-dioxane (0.3 mL), and the mixture was stirred at 0°C. for 5 min. The mixture concentrated under reduced pressure and theresidue was purified by reverse-phase preparative HPLC using a mixtureof water (5% CH₃CN, 0.05% HOAc) and CH₃CN (0.05% HOAc) as the mobilephase and Phenomenex Luna C-18 column as the stationary phase to afford(1R,2R)-2-((6-((5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolas a solid (1.38 mg, 5%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.36 (s, 1H), 8.00(d, J=7.4 Hz, 1H), 7.62 (d, J=5.9 Hz, 2H), 7.47 (d, J=8.9 Hz, 1H), 7.31(d, J=8.4 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.18 (dd, J=1.2, 8.1 Hz, 1H),6.14 (br s, 1H), 5.44 (s, 2H), 3.47-3.57 (br m, 2H), 2.94 (t, J=5.4 Hz,2H), 2.40 (br s, 2H), 2.02 (d, J=11.8 Hz, 1H), 1.85-1.87 (m, 6H),1.57-1.66 (m, 2H), 1.12-1.30 (m, 4H); LCMS (ESI) m/z 460 (M+H)⁺.

Example 226 Preparation of(1R,2R)-2-((6-((5-(1H-imidazol-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

A stirred mixture of(1R,2R)-2-((6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(250 mg, 0.50 mmol) from Step 5 of Example 183, imidazole (80 mg, 1.18mmol), potassium carbonate (82 mg, 0.59 mmol),trans-N,N-dimethylcyclohexane-1,2-diamine (9 mg, 0.063 mmol), copper (I)iodide (30 mg, 0.158 mmol) and DMF (2 mL) was heated at 120° C. for 3 h.The reaction mixture was cooled to rt and partitioned between EtOAc andwater. The organic layer was separated, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by silicagel flash chromatography, eluting with 20:1 DCM: MeOH, to afford(1R,2R)-2-((6-((5-(1H-imidazol-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(78 mg, 35%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.52 (s, 1H),8.18 (s, 1H), 7.91-7.96 (m, 2H), 7.72-7.86 (m, 3H), 7.47 (dd, J=8.4, 1.8Hz, 1H), 7.30 (d, J=8.1 Hz, 1H), 7.21 (dd, J=8.1, 1.5 Hz, 1H), 7.07 (d,J=1.2 Hz, 1H), 5.52 (s, 2H), 4.71 (d, J=5.1 Hz, 1H), 3.51 (m, 1H), 3.38(m, 1H), 2.02 (m, 1H), 1.88 (m, 1H), 1.60-1.80 (m, 2H), 1.15-1.28 (m,4H); LCMS (ESI) m/z 445 (M+H)⁺.

Example 227 Preparation of(1R,2R)-2-((6-((5-(2-methyl-2H-tetrazol-5-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

(1R,2R)-2-((6-((5-(2-Methyl-2H-tetrazol-5-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol(18 mg, 18%) was obtained as a solid using a procedure analogous to thatdescribed in Step 5 of Example 203, substituting6-((5-(2-methyl-2H-tetrazol-5-yl)-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole from Step 6 of Example 236 for6-((5-bromo-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole used in Example 203. ¹H NMR (300 MHz, DMSO-d₆)δ 8.53 (s, 1H), 8.29 (s, 1H), 7.91-7.97 (m, 2H), 7.68-7.76 (m, 2H),7.21-7.32 (m, 2H), 5.52 (s, 2H), 4.72 (d, J=5.1 Hz, 1H), 4.42 (s, 3H),3.51 (m, 1H), 3.38 (m, 1H), 2.02 (m, 1H), 1.88 (m, 1H), 1.60-1.80 (m,2H), 1.15-1.28 (m, 4H); LCMS (ESI) m/z 461 (M+H)⁺.

Example 228 Preparation of(1S,2R,3R)-3-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol

To a stirred mixture of NMO in tert-butanol (5 mL), THF (1.5 mL), H₂O(0.5 mL), and a 4% wt solution of OsO₄ in H₂O (10 μL, 0.3 mmol) at rtwas added portionwise(R)—N-(cyclohex-2-en-1-yl)-6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-amine(142 mg, 0.4 mmol) from Example 176. After the mixture was stirred at rtfor 18 h, it was partitioned between EtOAc (200 mL) and 0.5 M aq K₂CO₃(100 mL). The organic layer was separated, washed with brine (100 mL),dried over MgSO₄, filtered, and concentrated under reduced pressure. Theresidue was purified twice by reverse-phase preparative HPLC elutingwith a mixture of water (5% CH₃CN, 0.05% HCOOH) and CH₃CN (0.05% HCOOH)as the mobile phase and Varian Pursuit XRs C18 column as the stationaryphase to afford(1S,2R,3R)-3-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol(7 mg, 2%) as a white powder. ¹H NMR (500 MHz, DMSO-d₆) δ 8.67 (s, 1H),8.40 (m, 1H), 8.07 (dd, J=2.6, 9.5 Hz, 1H), 7.95 (d, J=7.9 Hz, 1H), 7.66(d, J=1.2 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.21 (dd, J=1.6, 8.2 Hz, 1H),5.47 (s, 2H), 4.45-4.70 (m, 2H), 3.88 (br s, 1H), 3.76 (m, 1H), 3.43 (m,1H), 1.40-1.62 (m, 5H), 1.25 (m, 1H); LCMS (ESI) m/z 414 (M+H)⁺.

Example 229 Preparation of(1R,2S,3R)-3-((6-((7-(1H-pyrazol-1-yl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol

Step 1: A 20 mL reaction vessel was charged with 4-iodopyridin-2-amine(1.5 g, 6.8 mmol) and 1H-pyrazole (4.0 g, 58.9 mmol). Concentratedhydrochloric acid (1.5 ml) and 1,4-dioxane (1.5 mL) were added, and thereaction vessel was sealed. The mixture was irradiated in a microwaveoven at 120° C. for 45 min and then at 130° C. for 60 min. The mixturewas cooled to rt and then diethyl ether (6 ml) and ethanol (3 ml) wereadded. The mixture was sonicated for 10 min, and the solid was collectedby filtration and washed with diethyl ether and n-hexane to give4-(1H-pyrazol-1-yl)pyridin-2-amine hydrochloride (1.2 g, 90%) as a whitesolid. LCMS (ESI) m/z 161 (M+H)⁺.

Step 2:6-((7-(1H-pyrazol-1-yl)imidazo[1,2-a]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole(176 mg, 63%) was obtained as a yellow solid using a procedure analogousto that described in Step 6 of Example 117, substituting4-(1H-pyrazol-1-yl)pyridin-2-amine hydrochloride from Step 1 of thisExample for 2-aminoisonicotinonitrile used in Example 117, and addingNaHCO₃ to the reachion mixture. LCMS (ESI) m/z 378 (M+H)⁺.

Step 3:(1R,2S,3R)-3-((6-((7-(1H-Pyrazol-1-yl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol(25 mg, 12%) was obtained as a light tan solid using proceduresanalogous to those described in Steps 7-8 of Example 117, substituting6-((7-(1H-pyrazol-1-yl)imidazo[1,2-a]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazolefor3-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridine-7-carbonitrileused in Step 7 of Example 117, and substituting the product of thatreaction and (1R,2S,3R)-3-aminocyclohexane-1,2-diol hydrochloride,respectively, for 3-((2-(methylsulfinyl)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridine-7-carbonitrile and (1R,2R)-2-amino cyclohexanolused in Step 8 of Example 117. ¹H NMR (500 MHz, DMSO-d₆) δ 8.66 (d,J=2.5 Hz, 1H), 8.32 (d, J=7.4 Hz, 1H), 7.99 (s, 1H), 7.85 (d, J=7.9 Hz,1H), 7.79 (s, 1H), 7.54 (s, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.43 (s, 1H),7.28 (d, J=7.9 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 6.59 (s, 1H), 4.53 (d,J=5.9 Hz, 1H), 4.43 (d, J=3.9 Hz, 1H), 4.31 (s, 2H), 3.93 (d, J=3.9 Hz,1H), 3.80 (br s, 1H), 3.37-3.45 (m, 1H), 1.92 (dd, J=3.4, 11.8 Hz, 1H),1.65 (dd, J=5.2, 16.5 Hz, 1H), 1.51-1.61 (m, 1H), 1.32-1.48 (m, 2H),1.14-1.29 (m, 1H). LCMS (ESI) m/z 461 (M+H)⁺.

Example 230 Preparation of(1R,2S,3R)-3-((6-((5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol

Step 1:4-Methoxy-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroaniline(5.2 g, 92%) was obtained as a red solid using a procedure analogous tothat described in Step 1 of Example 127, substituting4-methoxy-2-nitroaniline for 4-methyl-2-nitroaniline used in Example127. ¹H NMR (500 MHz, DMSO-d₆) δ 8.64 (t, J=6.1 Hz, 1H), 7.98 (m, 1H),7.80 (d, J=8.4 Hz, 1H), 7.52 (d, J=3.1 Hz, 1H), 7.45 (dd, J=8.4, 1.5 Hz,1H), 7.18 (dd, J=9.4, 3.1 Hz, 1H), 6.91 (d, J=9.5 Hz, 1H), 4.72 (d,J=6.1 Hz, 2H), 3.72 (s, 3H), 2.77 (s, 3H); LCMS (ESI) m/z 362 (M+H)⁺.

Step 2:4-Methoxy-N¹-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine(4 g, 84%) was obtained as an oil using a procedure analogous to thatdescribed in Step 2 of Example 129, substituting4-methoxy-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroanilinefrom the previous step for4-fluoro-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroanilineused in Example 129. LCMS (ESI) m/z 332 (M+H)⁺.

Step 3:6-((5-Methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole(1.12 g, 27%) was obtained as a solid using a procedure analogous tothat described in Step 3 of Example 129, substituting4-methoxy-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diaminefrom the previous step for4-fluoro-N¹-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamineused in Example 129. ¹H NMR (500 MHz, DMSO-d₆) δ 8.35 (s, 1H), 7.97 (d,J=1.2 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.38-7.41 (m, 2H), 7.18 (d, J=2.3Hz, 1H), 6.82 (dd, J=8.8, 2.3 Hz, 1H), 5.55 (s, 2H), 3.75 (s, 3H), 2.76(s, 3H); LCMS (ESI) m/z 342 (M+H)⁺.

Step 4:6-((5-Methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole(986 mg, 84%) was obtained as a solid using a procedure analogous tothat described in Step 4 of Example 129, substituting6-((5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazolefrom the previous step for6-((5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazoleused in Example 129. ¹H NMR (500 MHz, DMSO-d₆) δ 8.38 (s, 1H), 8.21 (d,J=1.2 Hz, 1H), 8.06 (d, J=8.4 Hz, 1H), 7.55 (dd, J=8.5, 1.6 Hz, 1H),7.38 (d, J=8.8 Hz, 1H), 7.19 (d, J=2.3 Hz, 1H), 6.83 (dd, J=8.8, 2.3 Hz,1H), 5.64 (s, 2H), 3.75 (s, 3H), 3.05 (s, 3H); LCMS (ESI) m/z 358(M+H)⁺.

Step 5:(1R,2S,3R)-3-((6-((5-Methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol(53 mg, 15%) was obtained as a solid using a procedure analogous to thatdescribed in Step 5 of Example 232, substituting6-((5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole,prepared as described in the previous step for6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazolefrom Example 232. ¹H NMR (500 MHz, DMSO-d₆) δ 8.31 (s, 1H), 7.92 (d,J=7.9 Hz, 1H), 7.62 (s, 1H), 7.40 (d, J=8.9 Hz, 1H), 7.29 (d, J=8.1 Hz,1H), 7.13-7.20 (m, 2H), 6.82 (dd, J=2.1, 8.7 Hz, 1H), 5.41 (s, 2H), 4.52(d, J=5.9 Hz, 1H), 4.43 (d, J=3.7 Hz, 1H), 3.93 (d, J=4.4 Hz, 1H), 3.79(m, 1H), 3.75 (s, 3H), 3.40 (m, 1H), 1.91 (dd, J=3.8, 12.4 Hz, 1H),1.51-1.70 (m, 2H), 1.32-1.45 (m, 2H), 1.20 (m, 1H); LCMS (ESI) m/z 425(M+H)⁺.

Example 231 Preparation of(1R,2S,3R)-3-((6-((7-(2H-1,2,3-triazol-2-yl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol

Step 1: 4-(2H-1,2,3-triazol-2-yl)pyridin-2-amine (370 mg, 39%) wasobtained as a white solid using a procedure analogous to that describedin Example 141, substituting 4-iodopyridin-2-amine and 1,2,3-triazole,respectively, for(1R,2R)-2-((6-((6-iodo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanoland pyrazole used in Example 141. LCMS (ESI) m/z 162 (M+H)⁺.

Step 2:6-((7-(2H-1,2,3-Triazol-2-yl)imidazo[1,2-a]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole(87 mg, 31%) was obtained as a yellow solid using a procedure analogousto that described in Step 6 of Example 117, substituting4-(2H-1,2,3-triazol-2-yl)pyridin-2-amine from Step 1 of this Example for2-aminoisonicotinonitrile used in Example 117, and adding NaHCO₃ to thereaction mixture. LCMS (ESI) m/z 379 (M+H)⁺.

Step 3:(1R,2S,3R)-3-((6-((7-(2H-1,2,3-Triazol-2-yl)imidazo[1,2-a]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol(35 mg, 33%) was obtained as a light tan solid using proceduresanalogous to those described in Steps 7-8 of Example 117, substituting6-((7-(2H-1,2,3-triazol-2-yl)imidazo[1,2-a]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazolefrom Step 2 of this Example for3-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridine-7-carbonitrileused in Step 7 of Example 117, and substituting the product of thatreaction and (1R,2S,3R)-3-aminocyclohexane-1,2-diol hydrochloride,respectively, for 3-((2-(methylsulfinyl)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridine-7-carbonitrile and (1R,2R)-2-amino cyclohexanolused in Step 8 of Example 117. ¹H NMR (500 MHz, DMSO-d₆) δ 8.40 (d,J=7.4 Hz, 1H), 8.19 (s, 2H), 8.04 (s, 1H), 7.85 (d, J=7.9 Hz, 1H), 7.63(dd, J=2.0, 7.4 Hz, 1H), 7.54 (s, 1H), 7.51 (s, 1H), 7.29 (d, J=8.4 Hz,1H), 7.12 (d, J=8.4 Hz, 1H), 4.49-4.69 (m, 1H), 4.43 (br s, 1H), 4.34(s, 2H), 3.93 (d, J=3.9 Hz, 1H), 3.80 (br s, 1H), 3.40 (d, J=8.4 Hz,2H), 1.92 (dd, J=3.9, 12.3 Hz, 1H), 1.66 (dd, J=5.4, 10.8 Hz, 1H),1.51-1.61 (m, 1H), 1.31-1.48 (m, 2H), 1.12-1.29 (m, 1H). LCMS (ESI) m/z461 (M+H)⁺.

Example 232 Preparation of(1R,2S,3R)-3-((6-((5-vinyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol

Step 1: N-(4-Iodo-2-nitrophenyl)formamide was synthesized as a blacksolid (7.4 g, 71%) using a procedure analogous to that described in Step1 of Example 162, substituting 4-iodo-2-nitroaniline for5-fluoro-3-nitropyridin-2-amine used in Example 162. LCMS (ESI) m/z 293(M+H)⁺.

Step 2:N-(4-Iodo-2-nitrophenyl)-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)formamidewas synthesized as an brown solid (9.7 g, 82%) using a procedureanalogous to that described in Step 3 of Example 47, substitutingN-(4-Iodo-2-nitrophenyl)formamide from the previous step for5-bromo-6-methoxy-1H-benzo[d]imidazole used in Example 47. LCMS (ESI)m/z 486 (M+H)⁺.

Step 3: A stirred mixture ofN-(4-iodo-2-nitrophenyl)-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)formamideand iron powder (16.7 g, 20 mmol) in EtOH (140 mL) and HOAc (60 mL) washeated at reflux for 1 h. The mixture was cooled to rt and filtered, andthe filtrate was concentrated under reduced pressure. The residue waspartitioned between EtOAc (200 mL) and 0.5 M aq Na₂CO₃ (100 mL). Theorganic layer was separated and further washed with brine (100 mL),dried over MgSO₄, filtered, and concentrated under reduced pressure toafford6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole(5.9 g, 68%) as a yellow solid that did not require furtherpurification. ¹H NMR (500 MHz, DMSO-d₆) δ 8.44 (s, 1H), 8.03 (d, J=1.0Hz, 1H), 7.97 (s, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.49 (dd, J=1.4, 8.5 Hz,1H), 7.37-7.43 (m, 2H), 5.60 (s, 2H), 2.76 (s, 3H); LCMS (ESI) m/z 438(M+H)⁺.

Step 4:6-((5-Iodo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazolewas synthesized as a white foam (2.9 g, 94%) using a procedure analogousto that described in Step 6 of Example 36, substituting6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazolefrom the previous step for the6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole usedin Example 36. ¹H NMR (500 MHz, DMSO-d₆) δ 8.47 (s, 1H), 8.21 (s, 1H),8.02-8.10 (m, 2H), 7.56 (dd, J=1.4, 8.5 Hz, 1H), 7.50 (dd, J=1.2, 8.4Hz, 1H), 7.40 (d, J=8.6 Hz, 1H), 5.69 (s, 2H), 3.05 (s, 3H); LCMS (ESI)m/z 454 (M+H)⁺.

Step 5: To a suspension of6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole(350 mg, 0.8 mmol) and (1R,2S,3R)-3-aminocyclohexane-1,2-diolhydrochloride (258 mg, 1.6 mmol), prepared as described in GauthierErrasti, et al, Org. Lett. 2009, 13, 2912-2915, in anhydrous DMA (1.5mL) was added DIEA (402 μL, 2.4 mmol). The mixture was heated in asealed tube at 120° C. for 15 h. The mixture was cooled to rt andpartitioned between EtOAc (150 mL) and 0.5 M aq K₂CO₃ (100 mL). Theorganic layer was separated and washed with brine (100 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by silica gel flash chromatography eluting with 5% MeOH inDCM to afford(1R,2S,3R)-3-((6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol(127 mg, 32%) as a yellow solid. LCMS (ESI) m/z 521 (M+H)⁺.

Step 6: A suspension of(1R,2S,3R)-3-((6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol(120 mg, 0.2 mmol), vinylboronic acid pinacol ester (71 mg, 0.5 mmol),and K₂CO₃ (64 mg, 0.5 mmol) in 6:1 dioxane:water (3.5 mL) was purgedwith argon for 5 min. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (19 mg, 0.02 mmol) was added to the mixture, themixture was purged with argon for an additional 5 min and then heated ina sealed tube at 100° C. for 6 h. The mixture was cooled to rt andpartitioned between EtOAc (150 mL) and 0.5 M aq K₂CO₃ (100 mL). Theorganic layer was separated and washed with brine (100 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by reverse-phase preparative HPLC using a mixture of water(5% CH₃CN, 0.05% HCOOH) and CH₃CN (0.05% HCOOH) as the mobile phase andVarian Pursuit XRs C18 column as the stationary phase to afford thenearly pure compound. This was further purified by silica gel flashchromatography, eluting isocraticlly with 5% MeOH in CH₂Cl₂, to afford(1R,2S,3R)-3-((6-((5-vinyl-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol(5 mg, 5%) as a white powder. ¹H NMR (500 MHz, MeOH-d₄) δ 8.28 (br s,1H), 7.69 (s, 1H), 7.54 (m, 1H), 7.41-7.43 (m, 2H), 7.37 (d, J=8.1 Hz,1H), 7.22 (m, 1H), 6.81-6.86 (m, 2H), 5.76 (d, J=17.7 Hz, 1H), 5.49 (s,2H), 5.19 (d, J=11.1 Hz, 1H), 3.99-4.02 (m, 2H), 3.50 (m, 1H), 2.08 (m,1H), 1.72-1.85 (m, 2H), 1.48-1.55 (m, 2H), 1.28-1.39 (m, 2H); LCMS (ESI)m/z 421 (M+H)⁺.

Example 233 Preparation of(1R,2S,3R)-3-((6-((5-(oxetan-3-yloxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol

Step 1: To a stirred solution of 4-amino-3-nitrophenol (1.37 g, 8.91mmol) in DMF (15 mL) at rt was added cesium carbonate (5.79 g, 17.82mmol) and the mixture was stirred for 30 min.Oxetan-3-yl-4-methylbenzenesulfonate (3.05 g, 13.36 mmol) was added andthe mixture was heated at 80° C. for 6 h. The mixture was cooled to rtand partitioned between EtOAc and water. The organic layer wasseparated, and the aqueous layer was extracted with additional EtOAc.The combined organic layers were washed with brine. The organic layerwas separated, dried over MgSO₄, filtered, and concentrated underreduced pressure. The solid residue was purified by trituration withdiethyl ether to afford 2-nitro-4-(oxetan-3-yloxy)aniline (1.33 g, 71%)as a brown solid. ¹H NMR (500 MHz, DMSO-d₆) δ 7.29 (br s, 2H), 7.15 (dd,J=9.2, 3.0 Hz, 1H), 7.10 (d, J=3.0 Hz, 1H), 7.02 (d, J=9.2 Hz, 1H), 5.24(pentet, J=4.9 Hz, 1H), 4.87-4.93 (m, 2H), 4.51-4.53 (m, 2H); LCMS (ESI)m/z 211 (M+H)⁺.

Step 2: A stirred mixture of acetic anhydride (15 mL, 161 mmol) andformic acid (6 mL, 161 mmol) was heated at 60° C. for 5 h. The mixturewas cooled to rt, then 2-nitro-4-(oxetan-3-yloxy)aniline (1.69 g, 8.02mmol) was added and the mixture was heated at 70° C. for 15 h. Themixture was cooled to rt and concentrated under reduced pressure. Theresidue was partitioned between EtOAc and saturated aq NaHCO₃. Theorganic layer was separated, dried over MgSO₄, filtered, andconcentrated under reduced pressure. The residue was purified by silicagel flash chromatography eluting with a gradient of 20% EtOAc in hexanesto 100% EtOAc to afford N-(2-nitro-4-(oxetan-3-yloxy)phenyl)formamide(967 mg, 51%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆) δ 10.36 (brs, 1H), 8.29 (m, 1H), 7.85 (d, J=8.9 Hz, 1H), 7.36 (d, J=1.8 Hz, 1H),7.24 (dd, J=9.0, 3.0 Hz, 1H), 5.38 (pentet, J=4.9 Hz, 1H), 4.92-4.94 (m,2H), 4.53-4.56 (m, 2H).

Step 3:N-((2-(Methylthio)benzo[d]thiazol-6-yl)methyl)-N-(2-nitro-4-(oxetan-3-yloxy)phenyl)formamide(1.71 g) was obtained as an oil using a procedure analogous to thatdescribed in Step 2 of Example 203, substitutingN-(2-nitro-4-(oxetan-3-yloxy)phenyl)formamide from Step 2 of thisExample for N-(4-bromo-2-fluoro-6-nitrophenyl)formamide used in Example203. LCMS (ESI) m/z 432 (M+H)⁺.

Step 4:2-(Methylthio)-6-((5-(oxetan-3-yloxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole(640 mg, 41% from N-(2-nitro-4-(oxetan-3-yloxy)phenyl)formamide) wasobtained as a solid using a procedure analogous to that described inStep 3 of Example 203, substitutingN-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-N-(2-nitro-4-(oxetan-3-yloxy)phenyl)formamidefrom the previous step forN-(4-bromo-2-fluoro-6-nitrophenyl)-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)formamideused in Example 203. ¹H NMR (500 MHz, DMSO-d₆) δ 8.38 (s, 1H), 7.98 (d,J=1.4 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.40 (dd,J=8.4, 1.8 Hz, 1H), 6.93 (d, J=2.3 Hz, 1H), 6.79 (dd, J=8.8, 2.3 Hz,1H), 5.55 (s, 2H), 5.27 (pentet, J=5.6 Hz, 1H), 4.91-4.94 (m, 2H),4.53-4.55 (m, 2H), 2.76 (s, 3H); LCMS (ESI) m/z 384 (M+H)⁺.

Step 5:2-(Methylsulfinyl)-6-((5-(oxetan-3-yloxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole(496 mg, 74%) was obtained as a white solid using a procedure analogousto that described in Step 4 of Example 130, substituting2-(methylthio)-6-((5-(oxetan-3-yloxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazolefrom the previous step for2-(methylthio)-6-((5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazoleused in Example 130. ¹H NMR (500 MHz, DMSO-d₆) δ 8.41 (s, 1H), 8.22 (m,1H), 8.07 (d, J=10.0 Hz, 1H), 7.56 (m, 1H), 7.42 (d, J=10.0 Hz, 1H),6.95 (d, J=5.0 Hz, 1H), 6.80 (m, 1H), 5.64 (s, 2H), 5.27 (pentet, J=5.0Hz, 1H), 4.92-4.95 (m, 2H), 4.52-4.55 (m, 2H), 3.05 (s, 3H); LCMS (ESI)m/z 400 (M+H)⁺.

Step 6:(1R,2S,3R)-3-((6-((5-(Oxetan-3-yloxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol(68 mg, 12%) was obtained as a solid using a procedure analogous to thatdescribed in Step 5 of Example 232, substituting2-(methylsulfinyl)-6-((5-(oxetan-3-yloxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazolefrom the previous step for6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazoleused in Example 232. ¹H NMR (500 MHz, DMSO-d₆) δ 8.34 (s, 1H), 7.92 (d,J=7.9 Hz, 1H), 7.63 (d, J=1.5 Hz, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.28 (d,J=8.2 Hz, 1H), 7.18 (dd, J=8.2, 1.6 Hz, 1H), 6.91 (d, J=2.3 Hz, 1H),6.79 (dd, J=8.8, 2.4 Hz, 1H), 5.41 (s, 2H), 5.27 (pentet, J=5.2 Hz, 1H),4.91-4.94 (m, 2H), 4.51-4.54 (m, 2H), 4.43 (d, J=3.8 Hz, 1H), 3.92 (brm, 1H), 3.79 (m, 1H), 3.38 (m, 1H), 3.31 (m, 1H), 1.91 (m, 1H),1.54-1.67 (m, 2H), 1.34-1.42 (m, 2H), 1.21 (m, 1H); LCMS (ESI) m/z 467(M+H)⁺.

Example 234 Preparation of(1R,2S,3R)-3-((6-((6-(1H-1,2,4-triazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol

Step 1:6-((6-(1H-1,2,4-Triazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole(108 mg, 19%) was obtained as a yellow solid using a procedure analogousto that described in Example 141, substituting6-((6-iodo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole,prepared as an intermediate product in Step 2 of Example 96, and1,2,4-triazole, respectively, for(1R,2R)-2-((6-((6-iodo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanoland pyrazole used in Example 141. LCMS (ESI) m/z 380 (M+H)⁺.

Step 2:(1R,2S,3R)-3-((6-((6-(1H-1,2,4-Triazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol(53 mg, 41%) was obtained as a yellow solid using procedures analogousto those described in Steps 7-8 of Example 117, substituting6-((6-(1H-1,2,4-triazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazolefrom Step 1 of this Example for3-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridine-7-carbonitrileused in Step 7 of Example 117, and substituting the product of thatreaction and (1R,2S,3R)-3-aminocyclohexane-1,2-diol hydrochloride,respectively, for 3-((2-(methylsulfinyl)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridine-7-carbonitrile and (1R,2R)-2-amino cyclohexanolused in Step 8 of Example 117. ¹H NMR (500 MHz, DMSO-d₆) δ 9.30 (s, 1H),8.89 (d, J=2.0 Hz, 1H), 8.76 (s, 1H), 8.56 (d, J=2.0 Hz, 1H), 8.29 (s,1H), 8.21 (s, 1H), 7.93 (d, J=7.9 Hz, 1H), 7.69 (s, 1H), 7.27-7.32 (m,1H), 7.20-7.27 (m, 1H), 5.54 (s, 2H), 4.44 (d, J=4.9 Hz, 2H), 3.93 (d,J=4.4 Hz, 1H), 3.79 (br s, 1H), 3.39 (d, J=8.4 Hz, 2H), 1.92 (dd, J=3.4,12.8 Hz, 1H), 1.61-1.71 (m, 1H), 1.50-1.61 (m, 1H), 1.30-1.47 (m, 2H),1.12-1.29 (m, 1H). LCMS (ESI) m/z 463 (M+H)⁺.

Example 235 Preparation of(1R,2S,3R)-3-((6-((5-morpholino-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol

A suspension of(1R,2S,3R)-3-((6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol(262 mg, 0.5 mmol) from Step 5 of Example 232, morpholine (264 μL, 3.0mmol), L-proline (23 mg, 0.2 mmol), and K₂CO₃ (209 mg, 1.5 mmol) in DMSO(2.0 mL) was purged with argon for 5 min. Copper (I) iodide (19 mg, 0.02mmol) was added, and the mixture was purged for an additional 5 min,then heated in a sealed tube at 110° C. for 2 h. The mixture was cooledto rt and filtered through Celite, and the filtrate was purified byreverse-phase preparative HPLC using a mixture of water (5% CH₃CN, 0.05%HCOOH) and CH₃CN (0.05% HCOOH) as the mobile phase and Varian PursuitXRs C18 column as the stationary phase, followed by silica gel flashchromatography eluting with 5% MeOH in CH₂Cl₂ to afford(1R,2S,3R)-3-((6-((5-morpholino-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol(2 mg, 1%) as a white powder. ¹H NMR (500 MHz, MeOH-d₄) δ 8.19 (s, 1H),7.50 (s, 1H), 7.31-7.39 (m, 2H), 7.16-7.23 (m, 2H), 7.05 (dd, J=2.0, 8.9Hz, 1H), 5.44 (s, 2H), 3.95-4.06 (m, 2H), 3.80-3.88 (m, 4H), 3.50 (dd,J=2.6, 9.2 Hz, 1H), 3.06-3.14 (m, 4H), 2.09 (m, 1H), 1.77-1.86 (m, 2H),1.48-1.53 (m, 2H), 1.33 (m, 1H); LCMS (ESI) m/z 480 (M+H)⁺.

Example 236 Preparation of(1R,2S,3R)-3-((6-((5-(2-methyl-2H-tetrazol-5-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol

Step 1: N-(4-Cyano-2-nitrophenyl)formamide was synthesized as a whitesolid (4.8 g, 100%) using a procedure analogous to that described inStep 1 of Example 162, substituting 4-cyano-2-nitroaniline for5-fluoro-3-nitropyridin-2-amine used in Example 162. LCMS (ESI) m/z 192(M+H)⁺.

Step 2:N-(4-Cyano-2-nitrophenyl)-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)formamidewas synthesized as an yellow foam (920 mg, 92%) using a procedureanalogous to that described in Step 3 of Example 47, substitutingN-(4-cyano-2-nitrophenyl)formamide from the previous step for5-bromo-6-methoxy-1H-benzo[d]imidazole used in Example 47. LCMS (ESI)m/z 385 (M+H)⁺.

Step 3:1-((2-(Methylthio)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrilewas synthesized as a white solid (694 mg, 86%) using a procedureanalogous to that described in Step 3 of Example 232, substitutingN-(4-cyano-2-nitrophenyl)-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)formamidefrom the previous step forN-(4-iodo-2-nitrophenyl)-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)formamideused in Example 232. LCMS (ESI) m/z 337 (M+H)⁺.

Step 4: A suspension of1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile(694 mg, 2.1 mmol), sodium azide (403 mg, 6.3 mmol), and ammoniumchloride (331 mg, 6.3 mmol) in DMF (3 mL) was heated in a sealed tube at125° C. for 15 h. The mixture was cooled to rt and a precipitate formed.The solid was collected by filtration to afford6-((5-(2H-tetrazol-5-yl)-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole(796 mg, 100%) as a yellow solid that did not require furtherpurification. ¹H NMR (500 MHz, DMSO-d₆) δ 8.41 (s, 1H), 8.19 (s, 1H),8.02 (s, 1H), 7.88 (dd, J=1.0, 8.4 Hz, 1H), 7.81 (d, J=8.6 Hz, 1H), 7.52(d, J=8.4 Hz, 1H), 7.45 (dd, J=1.4, 8.5 Hz, 1H), 7.15-7.30 (br s, 2H),5.60 (s, 2H), 2.76 (s, 3H); LCMS (ESI) m/z 380 (M+H)⁺.

Step 5: To a stirred mixture of6-((5-(2H-tetrazol-5-yl)-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole(796 mg, 2.1 mmol), Cs₂CO₃ (673 mg, 2.1 mmol), and DMF (10 mL) was addediodomethane (129 μL, 2.1 mmol). The mixture was heated at 60° C. for 6h. Additional iodomethane (30 μL, 0.5 mmol) was added and the mixturewas stirred at 60° C. for an additional 4 h. The mixture was cooled tort and partitioned between EtOAc (200 mL) and 0.5 M aq Na₂CO₃ (100 mL).The organic layer was separated and washed with brine (100 mL), driedover MgSO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel flash chromatography, eluting with 2%MeOH in CH₂Cl₂, to afford6-((5-(2-methyl-2H-tetrazol-5-yl)-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole(318 mg, 39%) as a white solid. The regiochemistry of the alkylation wasdetermined by 2-dimensional nuclear Overhauser effect (NOE) experiment.¹H NMR (500 MHz, DMSO-d₆) δ 8.58 (s, 1H), 8.31 (s, 1H), 8.03 (s, 1H),7.93 (dd, J=1.0, 8.4 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.73 (d, J=8.6 Hz,1H), 7.46 (dd, J=1.2, 8.4 Hz, 1H), 5.66 (s, 2H), 4.41 (s, 3H), 2.76 (s,3H); LCMS (ESI) m/z 394 (M+H)⁺.

Step 6:6-((5-(2-Methyl-2H-tetrazol-5-yl)-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole was synthesized as a white foam (390 mg) usinga procedure analogous to that described in Step 6 of Example 36,substituting6-((5-(2-methyl-2H-tetrazol-5-yl)-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazolefrom the previous step for6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole usedin Example 36. LCMS (ESI) m/z 410 (M+H)⁺.

Step 7: To a suspension of6-((5-(2-methyl-2H-tetrazol-5-yl)-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole(330 mg, 0.8 mmol) and (1R,2S,3R)-3-aminocyclohexane-1,2-diolhydrochloride (391 mg, 2.4 mmol), prepared as described in GauthierErrasti, et al, Org. Lett. 2009, 13, 2912-2915, in anhydrous NMP (3.0mL) was added DIEA (703 μL, 4.0 mmol). The mixture was heated in asealed tube at 120° C. for 15 h. Additional(1R,2S,3R)-3-aminocyclohexane-1,2-diol hydrochloride (258 mg, 1.6 mmol)and DIEA (703 μL, 4.0 mmol) were added, and the mixture was heated at140° C. for a further 15 h. The mixture was cooled to rt and waspurified by reverse-phase preparative HPLC using a mixture of water (5%CH₃CN, 0.05% HCOOH) and CH₃CN (0.05% HCOOH) as the mobile phase andVarian Pursuit XRs C18 column as the stationary phase to afford(1R,2S,3R)-3-((6-((5-(2-methyl-2H-tetrazol-5-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol(37 mg, 10%) as a white powder. ¹H NMR (500 MHz, DMSO-d₆) δ 8.53 (s,1H), 8.29 (s, 1H), 7.90-7.98 (m, 2H), 7.74 (d, J=8.4 Hz, 1H), 7.69 (s,1H), 7.31 (m, 1H), 7.23 (dd, J=1.5, 8.4 Hz, 1H), 5.52 (s, 2H), 4.41 (s,3H), 3.93 (m, 1H), 3.79 (m, 1H), 3.25 (m, 1H), 1.91 (m, 1H), 1.52-1.69(m, 3H), 1.32-1.44 (m, 2H), 1.15-1.25 (m, 2H); LCMS (ESI) m/z 477(M+H)⁺.

Example 237 M-NFS-60 Cell Proliferation Assay

The compounds disclosed herein were tested in an M-NFS-60 cellproliferation assay to determine their cellular potency against CSF1R.M-NFS-60s are mouse monocytic cells that depend on the binding of theligand M-CSF to its receptor, CSF1R, to proliferate. Inhibition of CSF1Rkinase activity will cause reduced growth and/or cell death. This assayassesses the potency of compounds as CSF1R inhibitors by measuring thereduction of Alamar Blue reagent by viable cells.

On day one of the experiment, M-NFS-60 cells were maintained in RPMIcomplete medium (Omega Scientific) plus 10% FBS supplemented with 20ng/mL of M-CSF (R&D Systems). 96-well TC-treated, flat bottom plateswere seeded at 10,000 cell/well at a volume of 100 μL per well. Thecells were cultured overnight at 37° C. under 5% CO₂.

On day two, compounds were added to the cells at 9 differentconcentrations, with half-log intervals alongside a control referencecompound serving as a positive control. Final DMSO concentration waskept at 0.5% for a final volume of 200 μL. The compounds were allowed toincubate with the cells for 72 hours at 37° C. under 5% CO₂.

On day five of the experiment, 40 μl of Alamar Blue reagent was added toeach well and allowed to incubate for 3 hours. Alamar Blue fluorescencewas read using SoftMax Pro software at 560 nm (excitation) and 590 nm(emission). IC₅₀s were generated as an average of duplicates andrepresents the concentration of test compound that achieves 50%inhibition of cellular proliferation compared to control.

In one embodiment, the compounds provided herein were found to have IC₅₀of about or less than about 5, 4, 3, 2, 1, 0.5, 0.1, 0.05 or 0.01 μM. Inanother embodiment, the compounds provided herein were found to haveactivity IC50 of about or less than about 2000, 1000, 500, 300, 100, 50,40, 30 or 20 nM. In another embodiment, the compounds provided hereinwere found to have activity IC50 of less than about 200 or 100 nM.

Example 238 HEK293 CSF1R Phosphorylation MSD Assay

The compounds disclosed herein were tested in a CSF1R phosphorylationassay to determine their cellular potency against CSF1R. A HEK293 cellline expressing CSF1R fused to FK506 binding protein (FKBP) as amolecular tag was generated. Inhibition of CSF1R kinase activity willprevent ligand-stimulated autophosphorylation of the CSF1R-FKBP inintact cells. Subsequent cell lysates are assayed in a sandwich ELISAemploying the electrochemiluminescent Meso Scale Discovery (MSD)technology for the presence of the phosphorylated (p)CSF1R-FKBP. Thisassay determines the potency of compounds as CSF1R inhibitors bymeasuring the reduction in the amount of pCSF1R with increasing doses ofcompounds added to the cells prior to M-CSF stimulation.

On day one of the experiment, HEK293-CSF1R-FKPB cells, maintained inDMEM, with L-glutamine (Mediatech), 10% FBS, and 100 units/mLPenicillin/Streptomycin, were seeded at 50,000 cell/well in a volume of100 μL per well in 96-well Cell Bind plates (Costar). The cells werecultured overnight at 37° C. under 5% CO₂. To prepare the plates used inthe MSD assay, a 330 nM biotin-FK506 (in TBS pH 7.2) solution was addedat 30 μL per well to streptavidin-coated 96-well plates (MSD), andincubated overnight at room temperature, shaking at 500 rpm on anorbital shaker.

On day two, compounds diluted in DMSO were added to the cells induplicate plates at 9 different concentrations with half-log intervals,plus DMSO only control, alongside a reference compound serving as apositive control. Final DMSO concentration was 0.5% in a volume of 200μL per well. The compounds were allowed to incubate with the cells for 2h at 37° C. under 5% CO₂. At the end of the incubation, human M-CSF (R&DSystems) was added for 5 min to a final concentration of 50 ng/mL tostimulate CSF1R phosphorylation. Cells were lysed for 20 min, and thelysates were applied to the washed, FK506-coated MSD plates, andincubated overnight at 4° C. shaking at 500 rpm.

On day three, the MSD plates were washed, and the captured CSF1R-FKBPwas assayed sequentially for phosphorylation using mouseanti-phosphotyrosine antibody (Millipore) and Sulfo-TAG goat anti-mouseIgG antibody (MSD), and detected on a Sector Imager 6000 instrument(MSD).

A single IC50 value for each compound was determined by averaging theIC₅₀s of the duplicates calculated using Igor Pro 6 software, andrepresents the compound concentration that achieves a 50% inhibition ofligand-induced CSF1R phosphorylation compared to DMSO control.

Example 239 Competition Binding Assay to Determine Selectivity Scoresand Binding Constants (Kd) of the Compounds Against a Panel of Kinases

Competition binding assays used herein were developed, validated andperformed as described in Fabian et al., Nature Biotechnology 2005, 23,329-336. Kinases were produced as fusions to T7 phage (See, Fabian etal. or WO04/015142) or alternatively, the kinases were expressed inHEK-293 cells and subsequently tagged with DNA for PCR detection (See,WO08/005310). For the binding assays, streptavidin-coated magnetic beadswere treated with biotinylated affinity ligands for 30 min at roomtemperature to generate affinity resins. The liganded beads were blockedwith excess biotin and washed with blocking buffer (SeaBlock (Pierce),1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reducenon-specific binding. Binding reactions were assembled by combiningkinase, liganded affinity beads, and test compounds in 1× binding buffer(20% SeaBlock, 0.17×PBS, 0.05% Tween 20, 6 mM DTT). Test compounds wereprepared as 100× stocks in DMSO and diluted into the aqueousenvironment. Kds were determined using an eleven point threefold serialdilutions. DMSO or control compounds were was added to control assayslacking a test compound. Primary screen assays were performed inpolypropylene 384-well plates in a final volume of 20-40 μL, while K_(d)determinations were performed in polystyrene 96-well plates in a finalvolume of 135 μL. The assay plates were incubated at room temperaturewith shaking for 1 hour to allow the binding reactions to reachequilibrium, and the affinity beads were washed extensively with washbuffer (1×PBS, 0.05% Tween 20) to remove unbound protein. The beads werethen resuspended in elution buffer (1×PBS, 0.05% Tween 20, 0.5 Mnon-biotinylated affinity ligand) and incubated at room temperature withshaking for 30 min. The kinase concentration in the eluates was measuredby quantitative PCR.

A selectivity score (S10) is a quantitative measure of selectivity of acompound against a panel of kinases. An S10 was calculated for acompound by dividing the number of kinases found to have a percent ofcontrol (DMSO) less than 10 by the total number of distinct kinasestested (excluding mutant variants). Percent of control (POC) iscalculated by subtracting the signal of the control compound (POC=0)from the signal of the test compound and dividing the outcome by thesignal of DMSO (POC=100) minus the signal of the control compound. Forthe compounds disclosed herein, S10 scores were obtained by testing thecompounds at 10 μM concentration in a kinase panel containing either 386or 392 distinct kinases.

In one embodiment, the compounds provided herein were found to have S10score of about or less than about 0.1, 0.08, 0.06, 0.04, 0.03, or 0.02.

The compounds provided herein were found to have the following activityshown in Table 1:

TABLE 1 CSF1R HEK293 M-NFS- pCSF1R Kinase CSF1R FLT3 KIT PDGFRβ 60 M-CSFspecif- Kd Kd Kd Kd CTB:IC₅₀ MSD:IC₅₀ icity Ex. # (nM) (nM) (nM) (nM)(nM) (nM) S(10) 1 B C B B B B ND 2 B B B B B A ND 3 A C B B B B B 4 A BB B B A ND 5 D D D D D D ND 6 B A B B B B ND 7 B B B A C B ND 8 B C C CD C ND 9 C C C C D C ND 10 B C C B C C ND 11 B B B B C C ND 12 D C D D DC ND 13 B C B B C B ND 14 D C D C D D ND 15 C D C D D C ND 16 C B B C DC ND 17 B B D B C C ND 18 A A A A B A ND 19 A C B B B B ND 20 C C D D DC ND 21 D D D D D C ND 22 B C B D C B ND 23 A A A B B A ND 24 D D D D DD ND 25 D D D D D D ND 26 B B D D D D ND 27 B C B B B B ND 28 B A A A BB ND 29 B B A B B A ND 30 A C A B B B ND 31 A C B B D D ND 32 D B D D DD ND 33 B B A A B B C 34 B A B B B B C 35 A A A A B A C 36 B D C D B B A37 D D D D D D A 38 C D C D C C A 39 A A A A A A C 40 A A A A A A B 41 BB B C B B A 42 A C A A B B B 43 B C B B B B B 44 B D C C B B A 45 A B AA A A B 46 A C B A B B B 47 B B A B A B B 48 B D C B B B A 49 B C C C BC A 50 A A A A A A C 51 A A A A A A C 52 A A A B B A C 53 B C B B A A B54 C D B B B B A 55 B C A A A A B 56 B B A A B B C 57 A B A A B B C 58 AC A A B B B 59 B C B B B B C 60 B C B A B B B 61 B A A A A A C 62 A B AA A A C 63 B A A A B B C 64 B B A A B C C 65 B C C D B B B 66 B D C B CB A 67 B C A B B B B 68 B C B B A A A 69 A C B A B B ND 70 A C A B B AND 71 B D D C C C ND 72 B D D C C B ND 73 B C B A B A A 74 B A B B B B B75 B C A A B B C 76 A A A A B B C 77 B C C C C B A 78 B A A A A A ND 79B B A A A A ND 80 B B A A A A B 81 C C B B D D B 82 B C C B C C A 83 A AC B B B A 84 B C B B B A A 85 A B A A A A B 86 B B A A B A C 87 A B A AA A B 88 A B A B A B ND 89 B C A A B B ND 90 B C B B B B ND 91 D A B B BD ND 92 B C A A B B ND 93 B B A A D D ND 94 B B B B A A ND 95 A D C A BB ND 96 B A A A A A C 97 B B A A A A B 98 B B A A A A B 99 D C D C D C A100 B C B B B B A 101 C B C B B B B 102 B B A A A A B 103 B D D B B B ND

In Table 1,

CSF1R Kd (nM): A≦5, 5<B≦20, 20<C≦50, D>50; and ND=no data;FLT3 Kd (nM): A≦200, 200<B≦1000, 1000<C≦5000, D>5000; and ND=no data;KIT Kd (nM): A≦100, 100<B≦500, 500<C≦2000, D>2000; and ND=no data;PDGFRβ Kd (nM): A≦50, 50<B≦500, 500<C≦2000, D>2000; and ND=no data;CSF1R Cell Proliferation Assay (M-NSF-60) IC₅₀ (nM): A≦50, 50<B≦400,400<C≦1500, D>1500; and ND=no data;HEK293 pCSF1R Assay (M-CSF MSD) IC₅₀ (nM): A≦50, 50<B≦200, 200<C≦500,D>500; and ND=no data; andS score: A≦0.01, 0.01<B≦0.02, C>0.02; and ND=no data.Additional compounds provided herein were found to have the followingactivity shown in Table 2:

TABLE 2 CSF1R HEK293 M-NFS- pCSF1R Kinase CSF1R FLT3 KIT PDGFRβ 60 M-CSFspecif- Kd Kd Kd Kd CTB:IC₅₀ MSD:IC₅₀ icity Ex. # (nM) (nM) (nM) (nM)(nM) (nM) S(10) 104 A A A A A A A 105 B B C C C C A 106 C B C C D D A107 B C B B B B B 108 B D C C B B A 109 C C B B B B A 110 A C B B B A A111 B C C C B B A 112 C C C C D C A 113 C C C D D C A 114 D C B C D B A115 D C C B B B A 116 B B B B D B ND 117 B D D B C D A 118 C C B Q C D A119 B B A A B B A 120 B C B B B B B 121 B C B B B B A 122 B B B B B B A123 B B A A B B B 124 B B A A B B B 125 B C C B C B B 126 B B B B B A A127 B C B A B B A 128 B D B B C C B 129 A C A A B A B 130 B C B A B C A131 A A A A A A B 132 A A A A B B C 133 B C B A B B A 134 B B B A B A A135 B D C C B B ND 136 B C A A B B B 137 A B A A A A A 138 A B A A A A A139 C B B B C C A 140 B D C B C C A 141 A B A A A A B 142 A A A A B A C143 B C C C C C B 144 A B B B B B B 145 A C B A B A A 146 B B A A B A B147 A B A A B A A 148 A C A B B B A 149 B C B A B C A 150 A B A B B B B151 B B A A B A B 152 B A A B B A B 153 B C C B B A A 154 B C C C B B A155 A A A B B A B 156 B C D C C C A 157 C D D C C D A 158 A B A A A A B159 B C C C C C A 160 A B A A A A A 161 B C B B B A A 162 A C B B B B A163 D D B B D D A 164 B C D C C D A 165 B D C C C D A 166 B B C D C D A167 A C B B A A A 168 B C D D C D A 169 B C C B B B A 170 D D D C D D A171 B B A A B A C 172 A B B B B A B 173 B B B B B B B 174 A A A A A A B175 B B B B B B A 176 B C B B C C B 177 A A A A A A C 178 B B C C C C B179 B C A A C C B 180 C C B B D D A 181 B C B A C C B 182 A B B B B A A183 A B A B A A B 184 B B A B B C A 185 B A A A B B B 186 B A B B C C B187 B D D C C B A 188 B C D C C B A 189 B B C C B C A 190 C B C C B D A191 C C B C D D A 192 B C B A C C B 193 B C A A A A A 194 B B A A B B B195 C C C C C C A 196 A B B B B A A 197 B D B B C D A 198 A C B A B C B199 B D D D D C A 200 B D C B B B A 201 C C C C D C A 202 B C B B B B A203 B B A B B B A 204 B C B B B B A 205 B B C B C D B 206 B B B B B B A207 B A A A A B B 208 A A A A A B B 209 B B B B B B A 210 C D C C D C A211 A A A A A A C 212 B B A A B B A 213 A B A A B B B 214 A D B B B A B215 B C C C B B A 216 B C C B B B A 217 B C C B B B A 218 B C C B B A A219 B C B A C B B 220 C D D B D D A 221 A A A A A A B 222 C D D C D D A223 B C B B B B A 224 B B A B D D A 225 A B A A C B ND 226 A B A A A A B227 B C B B A A B 228 D D C B D D A 229 B B A A B A A 230 B B A A A A A231 B C C B A A A 232 A A A A A A A 233 A B A A B A A 234 B B A A B B A235 B B A A B B A 236 B B B B B B A

In Table 2,

CSF1R Kd (nM): A≦5, 5<B≦20, 20<C≦50, D>50; and ND=no data;FLT3 Kd (nM): A≦200, 200<B≦1000, 1000<C≦5000, D>5000; and ND=no data;KIT Kd (nM): A≦100, 100<B≦500, 500<C≦2000, D>2000; and ND=no data;PDGFRβ Kd (nM): A≦50, 50<B≦500, 500<C≦2000, D>2000; and ND=no data;CSF1R Cell Proliferation Assay (M-NSF-60) IC₅₀ (nM): A≦50, 50<B≦400,400<C≦1500, D>1500; and ND=no data;HEK293 pCSF1R Assay (M-CSF MSD) IC₅₀ (nM): A≦50, 50<B≦200, 200<C≦500,D>500; and ND=no data; andS score: A≦0.01, 0.01<B≦0.02, C>0.02; and ND=no data.

Example 240 In Vivo Inhibition of the Growth and Survival of M-NFS-60Tumor Cells in Mice

1×10⁷ M-NFS-60 cells suspended in PBS were injected into the peritonealcavity of athymic nu/nu mice (Harlan Research Labs) in all study groupsexcept the naïve group, on Day 0. On Days 1-3, Compound A having theFormula I suspended in 0.5% hydroxypropylmethylcellulose (HPMC) wasdosed orally at 100, 30, and 10 and 3 mg/kg once a day (QD) in thetreatment group and compound Ki20227 suspended in Pharmatek#6 was dosedorally at 30 mg/kg once a day (QD) to the positive control group. Thevehicle control group received Pharmatek#6 once a day (QD) and the naivegroup was untreated. On Day 4, the peritoneal cavity was flushed with 5mL sterile PBS containing 40 units/mL sodium heparin and the peritonealcells were counted via the Vi-cell cell counter. FIG. 1 shows thedecrease in the number of tumor cells in the groups that wereadministered Compound A.

The same study was conducted using Compound B of having the Formula I,which was administered in the same formulation at the same dose andschedule. FIG. 2 shows the decrease in the number of tumor cells in thegroups that were administered Compound B.

Example 241 In Vivo Inhibition of PTHrP-Induced Hypercalcemia

Hypercalcemia of malignancy is a significant complication of advancedbreast and lung cancer, and multiple myeloma. Production of humoralfactors by the primary tumor is the mechanism responsible for 80% ofcases. The vast majority of HHM is caused by tumor-produced parathyroidhormone-related protein, which acts through PTH/PTHrP receptors in thebone and kidney to stimulate osteoclastic bone resorption and calciumresorption. Transforming growth factor-β (TGF-β), which is stored inbone matrix and released by osteoclastic bone resorption, brings aboutenhanced PTHrP production of tumor cells in bone. Increased productionof PTHrP accelerates further bone resorption and provides more space fortumor cell proliferation. Suppression of osteoclast-mediated boneresorption may therefore be effective against bone metastasis. M-CSF hasbeen shown to induce osteoclast generation and bone resorption andtherefore CSF1R inhibition may be an effective mechanism against bonemetastasis.

In this humoral hypercalcemia of malignancy model, 32-day-old BDF1 mice(Charles River Laboratories) in all groups except naïve were challengedtwice daily (morning and evening, by subcutaneous injection) with 0.5mg/kg recombinant PTHrP (Bachem, Torrance, Calif.) for seven days. Thetreatment group was administered Compound A of Formula I suspended in0.5% hydroxypropylmethylcellulose (HPMC) at 100, 30, and 10 and 3 mg/kgorally once a day (QD) for seven days On day 1, rPTHrP was injectedimmediately prior to dosing of Compound A or Vehicle Control. Thepositive control group was administered compound Ki20227 suspended inPharmatek#6 and was dosed orally at 30 mg/kg once a day (QD) while thevehicle control group received 1% hydroxypropylmethylcellulose orallyonce daily for seven days. The study groups are summarized in Table 3below. Mandibular blood was drawn exactly 3 hr after last dose tomonitor changes in blood ionized calcium and TRAPC5b levels (a boneresorption marker). Blood ionized calcium levels were determined using aQuantiChrom Calcium Assay Kit (DICA-500) for Quantitative ColorimetricCalcium Determination at 612 nm. TRAPC5b levels were determined usingmouse TRAP assay (Immunodiagnosticsystems Inc. # SB-TR103). Mice weresacrificed on Day8 and the tibiae were harvested for bone TRAP5b and H&Estaining.

TABLE 3 Group N Treatment Route/frequency 1 Naive 4 none n/a 2 PTHrP 40.5 mg/kg PTHrP SC BID 3 4 0.5 mg/kg PTHrP + SC BID and PO QD vehiclecontrol 1% HPMC 4 4 0.5 mg/kg PTHrP + SC BID and PO positive controlKi20227 30 mg/kg 5 5 0.5 mg/kg PTHrP + Sc BID and experimental 100 mg/kgCompound A PO QD 6 5 0.5 mg/kg PTHrP + SC BID and experimental 30 mg/kgCompound A PO QD 7 5 0.5 mg/kg PTHrP + SC BID and experimental 10 mg/kgCompound A PO QD 8 5 0.5 mg/kg PTHrP + SC BID and experimental 3 mg/kgCompound A PO QD

The results show that CSF1R inhibitors can be effective in this HHMmodel. FIG. 3 shows Compound A reduced serum TRAP5b levels in a doserelated manner and at the highest dose, reduced TRAP5b levels below thatof naïve animals.

The same study was conducted using Compound B having the Formula I,which was administered in the same formulation at the same dose andschedule. FIG. 4 shows Compound B reduced serum TRAP5b levels in a doserelated manner and at the highest dose, reduced TRAP5b levels below thatof naïve animals.

Example 242 In Vivo Inhibition of MCP-1 Induction

MCP-1 (monocyte chemo-attractant protein 1) is a chemokine thatregulates migration and infiltration of monocytes/macrophages and isimplicated in the development of tumor metastasis. It was demonstratedin prior experiments that M-CSF stimulation of human monocytes,peripheral blood mononuclear cells (PBMC) or whole blood, induced levelsof MCP-1. This experiment was conducted to see whether the sameobservations may be made in vivo.

In this study, 55-day old Balb/c mice (Harlan Laboratories) were groupedaccording to Table 4. One hour prior to M-CSF stimulation, animals weredosed orally with either Compound A, GW-2580 or vehicle. One hour postdose, animals were administered 0.8 μg each M-CSF resuspended in 200 μLsterile saline I.V. Two hours after administration of M-CSF, blood wascollected via the maxillary vein and processed for MCP-1 ELISA (R&DSystems # MJE00) according to the manufacturer's instructions.

TABLE 4 Group N Treatment MCSF Therapy (Dose) 1 3 Vehicle + sterilesaline Saline IV 1% HPMC 2 3 Vehicle + 0.8 μg/ms 200 μL IV 1% HPMCrM-CSF-CF 3 4 0.8 μg/ms rM-CSF-CF 200 μL IV Cmpd A (1 mg/kg) in saline 44 0.8 μg/ms rM-CSF-CF 200 μL IV Cmpd A (3 mg/kg) in saline 5 4 0.8 μg/msrM-CSF-CF 200 μL IV Cmpd A (10 mg/kg) in saline 6 4 0.8 μg/ms rM-CSF-CF200 μL IV Cmpd A (30 mg/kg) in saline 7 4 0.8 μg/ms rM-CSF-CF 200 μL IVCmpd A (100 mg/kg) in saline 8 4 0.8 μg/ms rM-CSF-CF 200 μL IV GW-2580(160 mg/kg) in saline 9 3 Naïve for base line none none

FIG. 5 shows that IV injection of M-CSF in mice induces the level ofMCP-1 approximately three-fold. The most potent MCP-1 reduction wasobserved at 60% at 100 mg/kg, and activity was reduced but comparable atthe 30 and 10 mg/kg (46 and 53%, respectively) by pretreatment withCompound A. The same study was conducted using Compound B having theFormula I, which was administered in the same formulation at the samedose and schedule. FIG. 6 also shows IV injection of M-CSF inducing athree-fold increase in MCP-1 levels. A dose response was less evident,but maximal activity was again observed at 100 mg/kg, and the %reduction (59%) was nearly identical to that measured for Compound A.

The embodiments described above are intended to be merely exemplary, andthose skilled in the art will recognize, or will be able to ascertainusing no more than routine experimentation, numerous equivalents ofspecific compounds, materials, and procedures. All such equivalents areconsidered to be within the scope of the claimed subject matter and areencompassed by the appended claims.

Since modifications will be apparent to those of skill in the art, it isintended that the claimed subject matter be limited only by the scope ofthe appended claims.

1-30. (canceled)
 31. A compound having Formula IX:

or a pharmaceutically acceptable salt thereof, wherein: R³ is hydrogen;each Q¹ is independently deuterium, halo, cyano, oxo, thioxo, alkyl,haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w), ═NOR^(d), or —C(═NR^(y))N(R^(y))OR^(x),where the alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q³ groups, in one embodiment, one to threeQ³ groups; each Q³ is independently selected from deuterium, halo,hydroxyl, alkyl, haloalkyl and hydroxyalkyl; Y is —(CR⁵R⁶)_(q)—; R⁵ andR⁶ are each independently hydrogen, halo, alkyl, haloalkyl orhydroxyalkyl; Z is O, S, or NH; W⁴ is N or CR^(11b); W⁵ is N or CR¹³;R^(11b) and R¹³ are each independently hydrogen or Q²; each Q² isindependently halo, deuterium, cyano, oxo, thioxo, alkyl, haloalkyl,haloalkenyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, heterocyclylalkyl, —R^(u)OR^(x),—R^(u)OR^(u)OR^(x), —R^(u)OR^(u)N(R^(y))(R^(z)), —R^(u)N(R^(y))(R^(z)),—R^(u)SR^(x), —R^(u)C(J)R^(x), —R^(u)C(J)OR^(x),—R^(u)C(J)N(R^(y))(R^(z)), —R^(u)C(J)R^(u)N(R^(y))(R^(z)),—R^(u)C(J)N(R^(y))OR^(x), —C(═NOR^(x))R^(x), —R^(u)S(O)_(t)R^(w),—R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w) or —C(═NR^(y))N(R^(y))OR^(x), where thealkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more groups Q⁴; in one embodiment, one to threeQ⁴ groups, each Q⁴ is independently selected from halo, deuterium,hydroxyl, alkyl, haloalkyl and hydroxyalkyl; Q⁵ and Q⁶ are eachindependently hydrogen, halo, cyano, alkyl, haloalkyl, aminoalkyl,alkenyl, alkynyl, cycloalkyl, heteroaryl, heteroaralkyl, heterocyclyl,heterocyclylalkyl, —R^(u)OR^(x), —R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x),—R^(u)C(J)R^(x), —R^(u)C(J)OR^(x), —R^(u)C(J)N(R^(y))(R^(z)),—R^(u)S(O)_(t)R^(w), —R^(u)N(R^(x))C(J)R^(x), —R^(u)N(R^(x))C(J)OR^(x),—R^(u)N(R^(x))S(O)_(t)R^(w) or —C(═NR^(y))N(R^(y))OR^(x), where thealkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl groups are optionallysubstituted with one or more Q⁸ groups; each Q⁸ is independentlyselected from halo, deuterium, hydroxyl, alkyl, haloalkyl andhydroxyalkyl; R^(d) is hydrogen or alkyl; each R^(u) is independentlyalkylene, alkenylene or a direct bond; R^(w) is alkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl; each R^(x) is independentlyhydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl,heteroaryl, or heteroaralkyl; R^(y) and R^(z) are each independentlyselected from (i) or (ii) below: (i) R^(y) and R^(z) are eachindependently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl,heteroaryl, or heteroaralkyl; or (ii) R^(y) and R^(z), together with thenitrogen atom to which they are attached, form a heterocyclyl orheteroaryl, optionally substituted with one or more, in one embodiment,one, two or three Q⁷ groups; each Q⁷ is independently selected fromhalo, deuterium, oxo, thioxo, hydroxy, alkoxy, alkyl, haloalkyl,hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl and heterocyclylalkyl; J is O, NR^(x) or S;each t is independently an integer from 0-2; n is 1 or 2; and q is aninteger from 0-4.
 32. The compound of claim 31 wherein Q⁵ and Q⁶ areeach independently hydrogen, halo, alkoxy, tetrazole or pyrazole, wherethe tetrazole and pyrazole rings are optionally substituted with one ortwo alkyl groups.
 33. The compound of claim 31, wherein Q⁵ and Q⁶ areeach independently hydrogen, chloro, fluoro, bromo or methoxy.
 34. Thecompound of claim 32, wherein q is
 0. 35. The compound of claim 34,wherein, Z is S.
 36. The compound of claim 34, wherein Z is O.
 37. Thecompound of claim 34, wherein W⁴ is N.
 38. The compound of claim 34,wherein W⁴ and W⁵ are each N.
 39. The compound of claim 34, wherein W⁴is N, and W⁵ is CH.
 40. The compound of claim 34, wherein Q¹ isR^(u)OR^(x).
 41. The compound of claim 40, wherein R^(u) is a bond. 42.The compound of claim 41, wherein R^(x) is hydrogen.
 43. A compoundhaving the following structure:

or a pharmaceutically acceptable salt thereof.
 44. A compound having thefollowing structure:

or a pharmaceutically acceptable salt thereof.
 45. A compound having thefollowing structure:

or a pharmaceutically acceptable salt thereof.
 46. A compound having thefollowing structure:

or a pharmaceutically acceptable salt thereof.
 47. A compound having thefollowing structure:

or a pharmaceutically acceptable salt thereof.
 48. A compound having thefollowing structure:

or a pharmaceutically acceptable salt thereof.
 49. A compound having thefollowing structure:

or a pharmaceutically acceptable salt thereof.
 50. A compound having thefollowing structure:

or a pharmaceutically acceptable salt thereof.
 51. A compound having thefollowing structure:

or a pharmaceutically acceptable salt thereof.
 52. A compound having thefollowing structure:

or a pharmaceutically acceptable salt thereof.
 53. A pharmaceuticalcomposition comprising a compound of claim 52 and a pharmaceuticallyacceptable carrier.